Advertisement

And Still They Come Over Troubled Waters: Can Asia’s Third-Generation EGFR Tyrosine Kinase Inhibitors (Furmonertinib, Aumolertinib, Rezivertinib, Limertinib, Befotertinib, SH-1028, and Lazertinib) Affect Global Treatment of EGFR+ NSCLC

  • Sally C.M. Lau
    Affiliations
    Department of Oncology, Laura & Issac Perlmutter Cancer Center, NYU Langone Health, NYU Grossman School of Medicine, New York, New York
    Search for articles by this author
  • Sai-Hong Ignatius Ou
    Correspondence
    Corresponding author. Address for correspondence: Sai-Hong Ignatius Ou, MD, PhD, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, 200 South Manchester Avenue, Suite 400, Orange, CA 92868.
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California
    Search for articles by this author

      Introduction

      Approximately 50% of patients with NSCLC diagnosed in Asia harbor the two canonical activating EGFR mutations (deletion exon 19, L858R) (EGFR+).
      • Midha A.
      • Dearden S.
      • McCormack R.
      EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII).
      The T790M gatekeeper mutation is the dominant acquired resistance mutation to first-generation (1G) and second-generation (2G) EGFR tyrosine kinase inhibitors (TKIs), which necessitated the development of third-generation (3G) EGFR TKI.
      • Nagasaka M.
      • Zhu V.W.
      • Lim S.M.
      • Greco M.
      • Wu F.
      • Ou S.I.
      Beyond osimertinib: the development of third-generation EGFR tyrosine kinase inhibitors for advanced EGFR+ NSCLC.
      Osimertinib is the first 3G EGFR TKI approved on the basis of a significant improvement in median progression-free survival (PFS) than platinum-based chemotherapy (hazard ratio [HR] = 0.30, 95% confidence interval [CI]: 0.23–0.41) in patients with EGFR T790M+ NSCLC in the AURA3 trial and an achieved investigator-assessed median PFS (mPFS) of 10.1 months.
      • Mok T.S.
      • Wu Y.-L.
      • Ahn M.-J.
      • et al.
      Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.
      By late September 2019, osimertinib was approved in 85 countries for the treatment of patients with EGFR T790M+ NSCLC.
      Contemporaneous development of several other 3G EGFR TKIs that are structurally distinct from osimertinib failed to reach regulatory approval or had their approval rescinded owing to a combination of adverse events, low efficacy, or rapidly changing treatment landscape.
      • Nagasaka M.
      • Zhu V.W.
      • Lim S.M.
      • Greco M.
      • Wu F.
      • Ou S.I.
      Beyond osimertinib: the development of third-generation EGFR tyrosine kinase inhibitors for advanced EGFR+ NSCLC.
      Until 2021, osimertinib was the only approved 3G EGFR TKI to treat EGFR T790M mutation. The monopoly of a single 3G EGFR TKI to treat 50% of patients with NSCLC in Asia had unintended consequences in cost and accessibility, which led to the recent development of 3G EGFR TKIs by homegrown companies in Asia.
      • Nagasaka M.
      • Zhu V.W.
      • Lim S.M.
      • Greco M.
      • Wu F.
      • Ou S.I.
      Beyond osimertinib: the development of third-generation EGFR tyrosine kinase inhibitors for advanced EGFR+ NSCLC.
      ,
      • Camidge D.R.
      Icotinib: kick-starting the Chinese anticancer drug industry.
      ,
      • Adjei A.A.
      Tackling the high cost of oncology drugs.
      The successful development and approval of the 1G EGFR TKI, icotinib, in the People’s Republic of China heralded the regional approach to tackle this major cancer burden.
      • Camidge D.R.
      Icotinib: kick-starting the Chinese anticancer drug industry.
      Our editorial discusses recent data published on limertinib, befotertinib, SH-1028, and rezivertinib in patients with previously treated T790M+ NSCLC
      • Shi Y.
      • Li B.
      • Wu L.
      • et al.
      Efficacy and safety of limertinib (ASK120067) in patients with locally advanced or metastatic EGFR T790M mutated non-small cell lung cancer: a multicenter, single-arm, phase 2b study [e-pub ahead of print]. J Thorac Oncol.
      • Shun L.
      • Zhang Y.
      • Zhang G.
      • et al.
      Efficacy and safety of befotertinib (D-0316) in patients with EGFR T790M mutated non-small cell lung cancer that had progressed after prior EGFR TKI therapy: a phase 2, multicenter, single-arm, open-label study [e-pub ahead of print]. J Thorac Oncol.
      • Xiong A.
      • Ren S.
      • Liu H.
      • et al.
      Efficacy and safety of SH-1028 in patients with EGFR T790M positive non-small-cell lung cancer: a multicenter, single-arm, open-label, phase 2 trial [e-pub ahead of print]. J Thorac Oncol.

      Shi Y, Wu S, Wang K, et al. Efficacy and safety of rezivertinib (BPI-7711) in patients with locally advanced or metastatic/recurrent EGFR T790M-mutated NSCLC: a phase IIb, multicenter, single-arm, open-label study [e-pub ahead of print]. J Thorac Oncol. https://doi.org/10.1016/j.jtho.2022.08.015, accessed September 20, 2022.

      with reference to similar data from osimertinib, aumolertinib, furmonertinib, and lazertinib.
      • Ahn M.J.
      • Tsai C.M.
      • Shepherd F.A.
      • et al.
      Osimertinib in patients with T790M mutation-positive, advanced non-small cell lung cancer: long-term follow-up from a pooled analysis of 2 phase 2 studies.
      • Zhou C.
      • Wang M.
      • Cheng Y.
      • et al.
      AURA17 study of osimertinib in Asia-Pacific patients (pts) with EGFR T790Mpositive advanced non-small cell lung cancer (NSCLC): updated phase II results including overall survival (OS).
      • Shi Y.
      • Hu X.
      • Zhang S.
      • et al.
      Efficacy, safety, and genetic analysis of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small-cell lung cancer: a phase 2b, multicentre, single-arm, open-label study.
      • Lu S.
      • Wang Q.
      • Zhang G.
      • et al.
      Efficacy of aumolertinib (HS-10296) in patients with advanced EGFR T790M+ NSCLC: updated post-national medical products administration approval results from the APOLLO registrational trial.
      • Cho B.C.
      • Han J.Y.
      • Kim S.W.
      • et al.
      A phase 1/2 study of lazertinib 240 mg in patients with advanced EGFR T790M-positive NSCLC after previous EGFR tyrosine kinase inhibitors.
      In addition, we reviewed the phase 3 data of aumolertinib

      Lu S, Dong X, Jian H, et al. AENEAS: a randomized phase III trial of aumolertinib versus gefitinib as first-line therapy for locally advanced or metastatic non-small-cell lung cancer with EGFR exon 19 deletion or L858R mutations [e-pub ahead of print]. J Clin Oncol. https://doi.org/10.1200/JCO.21.02641, accessed September 20, 2022.

      and furmonertinib

      Shi Y, Chen G, Wang X, et al. Furmonertinib (AST2818) versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (FURLONG): a multicentre, double-blind, randomised phase 3 study [e-pub ahead of print]. Lancet Respir Med. https://doi.org/10.1016/S2213-2600(22)00168-0, accessed September 20, 2022.

      in patients with treatment-naive NSCLC and their potential effect on the global treatment landscape with benchmark to FLAURA.
      • Soria J.C.
      • Ohe Y.
      • Vansteenkiste J.
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
      • Ramalingam S.S.
      • Vansteenkiste J.
      • Planchard D.
      • et al.
      Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC.
      • Cho B.C.
      • Chewaskulyong B.
      • Lee K.H.
      • et al.
      Osimertinib versus standard of care EGFR TKI as first-line treatment in patients with EGFRm advanced NSCLC: FLAURA Asian subset.

      3G EGFR TKIs in Previously Treated T790M+ NSCLC

      Currently, the seven pyrimidine-based 3G EGFR TKIs developed from Asia share a similar backbone with osimertinib with side-chain modifications (Fig. 1). The pivotal phase 2 trials of four of these compounds against EGFR T790M+ NSCLC were published in this issue of the Journal of Thoracic Oncology.
      • Shi Y.
      • Li B.
      • Wu L.
      • et al.
      Efficacy and safety of limertinib (ASK120067) in patients with locally advanced or metastatic EGFR T790M mutated non-small cell lung cancer: a multicenter, single-arm, phase 2b study [e-pub ahead of print]. J Thorac Oncol.
      • Shun L.
      • Zhang Y.
      • Zhang G.
      • et al.
      Efficacy and safety of befotertinib (D-0316) in patients with EGFR T790M mutated non-small cell lung cancer that had progressed after prior EGFR TKI therapy: a phase 2, multicenter, single-arm, open-label study [e-pub ahead of print]. J Thorac Oncol.
      • Xiong A.
      • Ren S.
      • Liu H.
      • et al.
      Efficacy and safety of SH-1028 in patients with EGFR T790M positive non-small-cell lung cancer: a multicenter, single-arm, open-label, phase 2 trial [e-pub ahead of print]. J Thorac Oncol.

      Shi Y, Wu S, Wang K, et al. Efficacy and safety of rezivertinib (BPI-7711) in patients with locally advanced or metastatic/recurrent EGFR T790M-mutated NSCLC: a phase IIb, multicenter, single-arm, open-label study [e-pub ahead of print]. J Thorac Oncol. https://doi.org/10.1016/j.jtho.2022.08.015, accessed September 20, 2022.

      Table 1 summarizes the trial conduct, patient and tumor characteristics, primary end points, clinical efficacies, and adverse events of these four compounds with comparison to previously published data of osimertinib, aumolertinib, furmonertinib and lazertinib.
      • Ahn M.J.
      • Tsai C.M.
      • Shepherd F.A.
      • et al.
      Osimertinib in patients with T790M mutation-positive, advanced non-small cell lung cancer: long-term follow-up from a pooled analysis of 2 phase 2 studies.
      • Zhou C.
      • Wang M.
      • Cheng Y.
      • et al.
      AURA17 study of osimertinib in Asia-Pacific patients (pts) with EGFR T790Mpositive advanced non-small cell lung cancer (NSCLC): updated phase II results including overall survival (OS).
      • Shi Y.
      • Hu X.
      • Zhang S.
      • et al.
      Efficacy, safety, and genetic analysis of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small-cell lung cancer: a phase 2b, multicentre, single-arm, open-label study.
      • Lu S.
      • Wang Q.
      • Zhang G.
      • et al.
      Efficacy of aumolertinib (HS-10296) in patients with advanced EGFR T790M+ NSCLC: updated post-national medical products administration approval results from the APOLLO registrational trial.
      • Cho B.C.
      • Han J.Y.
      • Kim S.W.
      • et al.
      A phase 1/2 study of lazertinib 240 mg in patients with advanced EGFR T790M-positive NSCLC after previous EGFR tyrosine kinase inhibitors.
      Figure thumbnail gr1
      Figure 1Structures of osimertinib, aumolertinib, furmonertinib, lazertinib, rezivertinib, limertinib, befotertinib, and SH-1028. The side chain modifications are highlighted in red.
      Table 1Efficacy and Adverse Events of 3G EGFR TKIs in T790M+ NSCLC From Asia
      Aumolertinib (Almonertinib, HS-10296)Furmonertinib (Alflutinib, AST2818)Lazertinib (YH25448, JNJ-73841937)Limertinib (ASK120067)Befotertinib (D-0136)
      Data from 75/100 mg cohort.
      SH-1028 (Formerly Oritinib)
      From the start of phase 1 dose escalation.
      Rezivertinib (BPI-7711)Osimertinib (AURA17)Osimertinib (AURA Extension/AURA2) Pooled Analysis
      Trial specifics
      n24422076301290227226171411
      Dose110 mg once daily80 mg once daily240 mg once daily160 mg twice daily75 mg once daily with dose increase to 100 mg after 3 wk if no grade 2 adverse event
      Of the patients, 26.9% did not dose escalate to 100 mg; 19.7% maintained dose at 75 mg.
      200 mg once daily180 mg once daily80 mg once daily80 mg once daily
      Plasma EGFR T790M+alone as enrollment criteriaNoNoNoAllowedAllowedNoAllowedNoNo
      Del19/L858R (%/%)63.5/34.862/3867.9/29.561.1/33.265.9/32.863.4/30.464.2/35.064/3568/29
      Stage III (%)12.3%4%3.8%3.0%1.7%0.4%1.3%1%4%
      Second line/>second line (%/%)
      Data from 75/100 mg cohort.
      76.6/23.477/2364.125.977.4/21.987.6/12.470.9/29.1NA31/6931.4/68.6
      Percentage brain metastasis (%)36.1%48%51.3%32.9%36.2%35.2%40.3%37%39%
      Asian (%)1001001001001001001009860
      Primary end pointBIRC-assessed ORRBIRC-assessed ORRBIRC-assessed ORRBIRC-assessed ORRBIRC-assessed ORRBIRC-assessed ORRBIRC-assessed ORRBIRC-assessed ORRBIRC-assessed ORR
      Enrollment period (mo)5 mo6 moNA20 mo
      During COVID-19 pandemic.
      7 mo29 mo
      During COVID-19 pandemic.
      6 moNANA
      Efficacy results
      ORR (%)68.9% (62.6%–74.6%)74% (68%–80%)55.3% (44.1%–66.4%)68.8% (63.2%–74.0%)67.6% (61.9%–71.9%)60.4% (53.7%–66.8%)64.6% (58%–70.8%)62% (54%–69%)66% (61%–70%)
      DOR (mo) (95% CI)15.1 (12.5–16.6)NR (8.4–NR)
      Data from 75/100 mg cohort.
      17.7 (9.9–NR)11.1 (9.6–13.8)12.4 (11.0–14.6)12.5 (11.2–NR)12.5 (10.0–13.9)9.9 (8.3–12.9)12.3 (11.1–13.8)
      mPFS (mo) (95% CI)12.4 (9.7–15.0)9.6 (8.2–9.7)11.1 (5.5–16.4)11.0 (9.7–12.4)16.6 (15.0–NE)12.6 (9.7–15.3)12.2 (9.6–13.9)9.79.9 (9.5–12.3)
      PFS rate (%) (95% CI)

      -6-mo PFS rate

      -12-mo PFS rate
      71.8 (65.6–77.1)

      51.7 (45.0–57.9)
      NA

      NA
      59.3 (46.9–69.8)

      48.0 (35.6–59.3)
      77.4 (71.6–82.2)

      47.1 (39.4–54.5)
      70.7 (63.8–76.5)

      52.9 (44.8–60.3)
      70.7 (63.8–76.5)

      52.9 (44.8–60.3)
      NA

      NA
      NA

      NA
      71 (64–77)

      44 (37–51
      mPFS (mo) (95% CI)

      -Brain mets present

      -No brain mets
      10.9 (7.0–13.8)

      16.5 (13.8–18.0)
      NA

      NA
      NA

      NA
      9.7 (5.9–11.6)12.5 (9.6–NR)

      17.9 (15.2–NR)
      8.3 (5.6–10.6)

      13.8 (12.4–NR)
      10.3 (7.0–12.5)

      12.4 (9.7–15.2)
      NA

      NA
      8.2 (6.9–9.7)

      12.4 (9.8–13.8)
      mPFS (mo)

      -del 19

      -L858R
      12.4 (9.7–15.0)

      12.3 (8.3–15.6)
      NA

      NA
      NA

      NA
      NA

      NA
      NA

      NA
      13.8 (12.2–NR)

      9.7 (5.6–NR)
      12.4 (8.8–15.1)

      10.3 (8.3–13.9)
      NA

      NA
      11.1 (9.7–13.1)

      9.5 (7.7–12.3)
      Adverse events
      Most common treatment-emergent adverse events (all grades) (%)CPK increase (20.9)

      Anemia (15.2)

      ALT increase (13.1)
      QT prolongation (15)

      AST increase (15)

      ALT increase (14)

      WBC decrease (12)
      Rash (37.2)

      Pruritus (34.6)

      Paresthesia (33.3)

      Headache (28.2)
      Diarrhea (81.7)

      Anemia (32.9)

      Rash (29.9)

      Anorexia (28.2)
      Thrombocytopenia (63.1)

      Headache (28.6)

      Leukopenia (25.5)

      Anemia (24.1)
      Diarrhea (41.6)

      CPK increase (28.0)

      Anemia (18.5)

      WBC decrease (15.7)
      Decrease WBC (27.9)

      Decrease platelet (23.0)

      Anemia (22.6)
      Diarrhea (35)

      Rash (30)

      Cough (25)
      Diarrhea (49)

      Rash (49)

      Dry skin (36)

      Paronychia (34)
      Notable adverse events (%)
      Not often associated OR high incidence with EGFR TKIs.
      CPK increase (20.9)QT prolongation (15)Headache (28.2)Diarrhea (81.7)Thrombocytopenia (63.1)

      Headache (28.6)
      CPK increase (28)

      QT prolongation (8)
      QT prolongation (5.3)Back pain (11)QT prolongation (5)
      3G, third-generation; ALT, alanine aminotransferase; BIRC, blinded independent review committee; CI, confidence interval; COVID-19, coronavirus disease 2019; CPK, creatinine phosphokinase; del 19, deletion exon 19; DoR, duration of response; mPFS, median progression-free survival; NA, not available; NE, not evaluable; NR, not reached; ORR, overall response rate; TKI, tyrosine kinase inhibitor.
      a Data from 75/100 mg cohort.
      b From the start of phase 1 dose escalation.
      c Of the patients, 26.9% did not dose escalate to 100 mg; 19.7% maintained dose at 75 mg.
      d During COVID-19 pandemic.
      e Not often associated OR high incidence with EGFR TKIs.
      Limertinib (ASK120067) was dosed at 160 mg twice daily, the only 3G EGFR TKI that is dosed twice daily. The incidence of treatment-related diarrhea from limertinib was unexpectedly high (81.7%), with 13.0% of patients experiencing grade greater than or equal to 3 diarrhea.
      • Shi Y.
      • Li B.
      • Wu L.
      • et al.
      Efficacy and safety of limertinib (ASK120067) in patients with locally advanced or metastatic EGFR T790M mutated non-small cell lung cancer: a multicenter, single-arm, phase 2b study [e-pub ahead of print]. J Thorac Oncol.
      Indeed, 27.2% of patients required a 50% dose reduction (80 mg twice daily). The independent review committee (IRC)–assessed overall response rates (ORRs) of patients with and without dose adjustment were 76.8% (95% CI: 66.2%–85.4%) and 65.8% (95% CI: 59.1%–72.0%), respectively. The mPFSs of patients with and without dose adjustment were 15.2 (95% CI: 11.0–19.3) months and 11.0 (95% CI: 8.9–12.4) months, respectively.
      • Shi Y.
      • Li B.
      • Wu L.
      • et al.
      Efficacy and safety of limertinib (ASK120067) in patients with locally advanced or metastatic EGFR T790M mutated non-small cell lung cancer: a multicenter, single-arm, phase 2b study [e-pub ahead of print]. J Thorac Oncol.
      Thus, the optimal dose of limertinib may be between 80 mg and 160 mg twice daily. An ongoing phase 3 trial of limertinib versus gefitinib has completed accrual (Table 2).
      Table 2Design of the Ongoing Pivotal Phase 3 Trials of the 3G EGFR TKIs From Asia
      CompoundsLazertinibRezivertinibLimertinibBefotertinibSH-1028
      Trial nameLASER301NANANANA
      Principal investigatorByoung Chul ChoYuankai ShiYuankai ShiShun LuCaicun Zhou
      Double blindYesYesYesNoYes
      Placebo controlledYesYesYesNoYes
      Comparison armGefitinibGefitinibGefitinibIcotinibGefitinib
      Stratification factorsDel19 vs. L858R

      Asian vs. non-Asians
      Del19 vs. L858R

      Brain mets (yes/no)
      Del19 vs. L858R

      Brain mets (yes/no)
      Del 19 vs. L858R

      Brain mets (yes/no)
      Del19 vs. L858R

      Brain mets (yes/no)
      Randomization1:11:11:11:12:1
      Primary end pointInvestigator-assessed PFSIRC-assessed PFSPFSIRC-assessed PFSInvestigator-assessed PFS
      Anticipated accrual number393294334362240
      MultinationalYes (Australia, Greece, Hungary, Republic of Korea, Malaysia, Philippines, Russian Federation, Serbia, Singapore, Taiwan, Thailand, Turkey, Ukraine)No (People’s Republic of China only)No (People’s Republic of China only)No (People’s Republic of China only)No (People’s Republic of China only
      Clinical trial number(s)NCT04248829CTR20190442CTR20191523

      NCT04143607
      CTR20192356

      NCT04206072
      CTR20192508

      NCT04239833
      ResultsOctober 202220232023End of 20222023
      Note: CTR number is for Chinese trial registration.
      Data for rezivertinib trial design from http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml. Accessed July 18, 2022.
      3G, third-generation; Del19, deletion exon 19; IRC, independent review committee; mets, metastasis; NA, not applicable; PFS, progression-free survival.
      Befotertinib (D-0136) used a step-up dosing regimen of 75 mg daily for 3 weeks (one cycle) and then escalated to 100 mg daily. Nevertheless, 26.9% (78 of 290) did not dose escalate to 100 mg, including 19.7% (57 of 290) of the patients who started at 75 mg daily and stayed at 75 mg daily dose owing to thrombocytopenia (59.6%, 34 of 57) or headache (33.3%, 19 of 57). In addition, 4.8% (14 of 290) had to reduce the dose to 50 mg daily owing to thrombocytopenia or investigator decision. Importantly, the ORR and mPFS of patients who started at 75 mg but did not have dose escalation was 57.7% (95% CI: 46.0%–68.8%) and 15.1 (95% CI: 9.8–19.4) months compared with those who have dose escalation to 100 mg with an ORR of 71.2% (95% CI: 64.6%–77.2%) and mPFS of 17.9 (95% CI: 15.0–not evaluable) months.
      • Shun L.
      • Zhang Y.
      • Zhang G.
      • et al.
      Efficacy and safety of befotertinib (D-0316) in patients with EGFR T790M mutated non-small cell lung cancer that had progressed after prior EGFR TKI therapy: a phase 2, multicenter, single-arm, open-label study [e-pub ahead of print]. J Thorac Oncol.
      The incidence of greater than or equal to grade 3 thrombocytopenia was 14.5%.
      • Shun L.
      • Zhang Y.
      • Zhang G.
      • et al.
      Efficacy and safety of befotertinib (D-0316) in patients with EGFR T790M mutated non-small cell lung cancer that had progressed after prior EGFR TKI therapy: a phase 2, multicenter, single-arm, open-label study [e-pub ahead of print]. J Thorac Oncol.
      Thus, it seems that the therapeutic window of befotertinib is narrow, where dose escalation is necessary for maximum clinical efficacy but toxicity may be dose limiting. The phase 3 trial of befotertinib versus icotinib will likely be presented at the end of 2022 (personal communication, Shun Lu) (Table 2).
      SH-1028 (formerly known as oritinib) was dosed at 200 mg once daily. Importantly, only 0.4% of the patient had localized disease, the lowest of all the phase 2 trials (Table 1).
      • Xiong A.
      • Ren S.
      • Liu H.
      • et al.
      Efficacy and safety of SH-1028 in patients with EGFR T790M positive non-small-cell lung cancer: a multicenter, single-arm, open-label, phase 2 trial [e-pub ahead of print]. J Thorac Oncol.
      The ORR was 60.4% (95% CI: 53.7%–66.8%) and the mPFS was 12.6 (95% CI: 9.7–15.3) months (Table 1). The unique adverse events of SH-1028 are asymptomatic creatinine phosphokinase (CPK) elevation at 28% (Table 1).
      • Xiong A.
      • Ren S.
      • Liu H.
      • et al.
      Efficacy and safety of SH-1028 in patients with EGFR T790M positive non-small-cell lung cancer: a multicenter, single-arm, open-label, phase 2 trial [e-pub ahead of print]. J Thorac Oncol.
      Nevertheless, SH-1028 was well tolerated at 200 mg once-daily dosing with a mean dose intensity of 100%.
      Rezivertinib was dosed at 160 mg once daily on the basis of results from a large-scale phase 1/2a dose-escalation study.
      • Shi Y.
      • Zhao Y.
      • Yang S.
      • et al.
      Safety, efficacy, and pharmacokinetics of rezivertinib (BPI-7711) in patients with advanced NSCLC with EGFR T790M mutation: a phase 1 dose-escalation and dose-expansion study.
      A total of 226 patients with EGFR T790M+ NSCLC were enrolled in a period of 5 months right before the coronavirus disease 2019 pandemic. The ORR by blinded independent central review was 64.6% (95% CI: 58.0%–70.8%) and mPFS was 12.2 (95% CI: 9.6–13.9) months. Most of the adverse events were myelosuppression and corrected QT interval prolongation at 5.3%.

      Shi Y, Wu S, Wang K, et al. Efficacy and safety of rezivertinib (BPI-7711) in patients with locally advanced or metastatic/recurrent EGFR T790M-mutated NSCLC: a phase IIb, multicenter, single-arm, open-label study [e-pub ahead of print]. J Thorac Oncol. https://doi.org/10.1016/j.jtho.2022.08.015, accessed September 20, 2022.

      Overall, unsurprisingly, the results of these four 3G EGFR TKIs were similar given the similarities in their structures. The clinical efficacies of all 3G EGFR TKIs were less against patients with EGFR L858R and those with central nervous system (CNS) metastases. We caution against cross-trial comparisons of PFS owing to differences in the patient composition of each trial (distribution of deletion exon 19/L858R, previous lines of treatment, tumor versus plasma detection of EGFR T790M mutation, proportions of CNS metastases, and the proportions of localized NSCLC [e.g., 12.3% in the aumolertinib trial, 4.0% in the furmonertinib trial, 1.3% in the rezivertinib trial, and 0.4% in the SH-1028 trial]) (Table 1). In addition, PFS was numerically higher among localized disease than metastatic disease as evidenced by a numerical difference in the mPFS of localized disease at 17.0 (95% CI: 8.3–19.4) months compared with 12.0 (95% CI: 9.6–13.8) months for metastatic disease for aumolertinib.
      • Lu S.
      • Wang Q.
      • Zhang G.
      • et al.
      Efficacy of aumolertinib (HS-10296) in patients with advanced EGFR T790M+ NSCLC: updated post-national medical products administration approval results from the APOLLO registrational trial.
      Furthermore, some of the trials (limertinib, befotertinib, and rezivertinib) allow patients with plasma-detected EGFR T790M+ found only by plasma genotyping to enroll. Patients with detectable EGFR T790M circulating tumor DNA generally had higher tumor burden and a poorer outcome from the AURA3 analysis.
      • Papadimitrakopoulou V.A.
      • Han J.Y.
      • Ahn M.J.
      • et al.
      Epidermal growth factor receptor mutation analysis in tissue and plasma from the AURA3 trial: osimertinib versus platinum-pemetrexed for T790M mutation-positive advanced non-small cell lung cancer.
      Indeed, numerically lower ORR and mPFS were achieved by patients with detectable plasma EGFR T790M+ NSCLC in the limertinib and rezivertinib trials. The ORR was 75.6% (95% CI: 65.8%–78.3%) and 60.7% (95% CI: 49.1%–70.2%) for patients with tumor- and plasma-detected EGFR T790M+ NSCLC treated with limertinib, respectively.
      • Shi Y.
      • Li B.
      • Wu L.
      • et al.
      Efficacy and safety of limertinib (ASK120067) in patients with locally advanced or metastatic EGFR T790M mutated non-small cell lung cancer: a multicenter, single-arm, phase 2b study [e-pub ahead of print]. J Thorac Oncol.
      The ORR and mPFS for patients on rezivertinib with tumor-detected EGFR T790M mutation were 70% (95% CI: 61%–78%) and 13.9 (95% CI: 11.3–17.9) compared to 56.9% (95% CI: 47.4%–66.1%) and 9.6 months (95% CI: 7.0–11.0).

      Shi Y, Wu S, Wang K, et al. Efficacy and safety of rezivertinib (BPI-7711) in patients with locally advanced or metastatic/recurrent EGFR T790M-mutated NSCLC: a phase IIb, multicenter, single-arm, open-label study [e-pub ahead of print]. J Thorac Oncol. https://doi.org/10.1016/j.jtho.2022.08.015, accessed September 20, 2022.

      Drug approvals on the basis of less robust study designs are sometimes necessary. Regulatory approval of osimertinib was also accelerated when acquired EGFR T790M mutation was identified as an area of great unmet need.
      • Shi Y.
      • Li B.
      • Wu L.
      • et al.
      Efficacy and safety of limertinib (ASK120067) in patients with locally advanced or metastatic EGFR T790M mutated non-small cell lung cancer: a multicenter, single-arm, phase 2b study [e-pub ahead of print]. J Thorac Oncol.
      In countries and regions where osimertinib is not easily accessible, approvals by local regulatory agencies on the basis of phase 2 data are not unreasonable and avoid delays in access to effective medicines. The fact that these trials enrolled quickly, over 5 to 7 months (before coronavirus disease 2019 pandemic), reflects the challenges patients face in accessing osimertinib, even in countries where it is approved. To date, aumolertinib and furmonertinib are approved in the People’s Republic of China and lazertinib is approved in the Republic of Korea for treatment of EGFR T790M mutations.
      • Nagasaka M.
      • Zhu V.W.
      • Lim S.M.
      • Greco M.
      • Wu F.
      • Ou S.I.
      Beyond osimertinib: the development of third-generation EGFR tyrosine kinase inhibitors for advanced EGFR+ NSCLC.
      ,
      • Wang F.
      • Adjei A.A.
      Does the lung cancer field need another third-generation EGFR tyrosine kinase inhibitor?.
      ,
      • Wang F.
      • Zhou Q.
      The challenges of third-generation EGFR tyrosine kinase inhibitors in the therapy of advanced NSCLC.
      Given the similar clinical efficacy revealed by the four other 3G EGFR TKIs, albeit with different adverse events profile, we anticipated that all of them should be approved by the Chinese National Medical Products Administration for treatment of EGFR T790M+ NSCLC. The degree of adoption of any of these new 3G EGFR TKIs in places where approved and available will depend on the cost, first-mover advantage, dosing schedule, side effects profiles, and the first-line phase 3 results.

      3G EGFR TKIs in Treatment-Naive EGFR+ NSCLC

      The most important utility of 3G EGFR TKI is the upfront treatment of advanced EGFR+ NSCLC on the basis of the statistical improvement in mPFS
      • Soria J.C.
      • Ohe Y.
      • Vansteenkiste J.
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
      and overall survival achieved by osimertinib over 1G EGFR TKIs.
      • Ramalingam S.S.
      • Vansteenkiste J.
      • Planchard D.
      • et al.
      Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC.
      As such, it is anticipated that the incidence of T790M+ NSCLC will eventually decrease, and the clinical data of these phase 2 trials on “Asian” 3G EGFR TKIs outlined in Table 1 may be of historical rather than clinical significance.
      Two of these EGFR TKIs, aumolertinib (AENEAS)

      Lu S, Dong X, Jian H, et al. AENEAS: a randomized phase III trial of aumolertinib versus gefitinib as first-line therapy for locally advanced or metastatic non-small-cell lung cancer with EGFR exon 19 deletion or L858R mutations [e-pub ahead of print]. J Clin Oncol. https://doi.org/10.1200/JCO.21.02641, accessed September 20, 2022.

      and furmonertinib (FURLONG),

      Shi Y, Chen G, Wang X, et al. Furmonertinib (AST2818) versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (FURLONG): a multicentre, double-blind, randomised phase 3 study [e-pub ahead of print]. Lancet Respir Med. https://doi.org/10.1016/S2213-2600(22)00168-0, accessed September 20, 2022.

      have completed phase 3 trials (Table 3). Both trials were well-conducted, double-blind, placebo-controlled trials and stratified for known prognostics factors—EGFR subtype and CNS metastasis. The AENEAS study revealed a statistically superior mPFS (HR by IRC = 0.50; 95% CI: 0.39–0.64, p < 0.0001) of aumolertinib over gefitinib. All patient subgroups benefited from aumolertinib, including those with known CNS metastases. Toxicities were consistent with what were reported in the phase 2 APOLLO with elevated CPK (34%) being the most common adverse event.

      Lu S, Dong X, Jian H, et al. AENEAS: a randomized phase III trial of aumolertinib versus gefitinib as first-line therapy for locally advanced or metastatic non-small-cell lung cancer with EGFR exon 19 deletion or L858R mutations [e-pub ahead of print]. J Clin Oncol. https://doi.org/10.1200/JCO.21.02641, accessed September 20, 2022.

      Furmonertinib was found to have clinical benefits when compared with gefitinib in previously untreated patients in the phase 3 FURLONG study reference. mPFS was superior with furmonertinib (HR by IRC = 0.44, 95% CI: 0.34–0.58, p < 0.0001) with benefit found across all subgroups. The most common toxicities were corrected QT interval prolongation (grades 1–2, 6%, and grade ≥ 3, 3%) and diarrhea. Quality of life, assessed using the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-L13, although statistically improved, was not clinically significant compared with that in gefitinib.

      Shi Y, Chen G, Wang X, et al. Furmonertinib (AST2818) versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (FURLONG): a multicentre, double-blind, randomised phase 3 study [e-pub ahead of print]. Lancet Respir Med. https://doi.org/10.1016/S2213-2600(22)00168-0, accessed September 20, 2022.

      Table 3List of Trial Characteristics, Clinical Efficacy, and Adverse Events of Randomized Phase 3 Trial of 3G EGFR TKI (Data Applied to the 3G EGFR TKI Arm)
      Trial nameAENEAS (n = 429)FURLONG (n = 357)FLAURA Asia Subset (n = 162)FLAURA Overall (n = 556)
      Trial characteristics
      Investigational 3G EGFR TKIAumolertinib 110 mg dailyFurmonertinib 80 mg dailyOsimertinib 80 mg dailyOsimertinib 80 mg daily
      SOC 1G EGFR TKIGefitinib 250 mg dailyGefitinib 250 mg dailyGefitinib 250 mg daily OR erlotinib 150 mg dailyGefitinib 250 mg daily OR erlotinib 150 mg daily
      Placebo-controlledYesYesYesYes
      Randomization1:11:11:11:1
      Stratification factorsEGFR del19 vs. L858R

      CNS mets: yes/no
      EGFR del19 vs. L858R

      CNS mets: yes/no
      EGFR del19 vs. L858R

      Race: Asian/non-Asian
      Stage IIIB/CAllowedAllowedAllowedAllowed
      CNS metastasisAsymptomatic (treated/untreated) allowedAsymptomatic (treated/untreated) allowedStable CNS mets allowedStable CNS mets allowed
      Primary end pointInvestigator-assessed PFSIRC-assessed PFSInvestigator-assessed PFSInvestigator-assessed PFS
      Stage IIIB/C6.8%4.8%4.9%5.2%
      CNS metastasis present26.8%33.9%20.4%20.9%
      EGFR subtypeDel19: 65.5%

      L858R: 34.4%
      Del19: 51.3%

      L858R: 48.7%
      NADel19: 62.7%

      L858R: 37.2%
      Positive smoking history30.1%23.8%35.8%21.2%
      Asian100%100%100%62.4%
      Median follow-up timeAumolertinib: 20.5 mo (95% CI: 18.0–20.6)

      Gefitinib: 20.7 mo (95% CI: 19.3–20.8)
      Furmonertinib: 21.0 mo (IQR: 18.0–23.5)

      Gefitinib: 21.0 mo (IQR: 18.0–23.5)
      Osimertinib: 13.8 mo

      Gefitinib/erlotinib: 10.7 mo
      Osimertinib: 15.0 mo (range: 0–25.1)

      Gefitinib/erlotinib (range: 0–26.1)
      Results (overall)
      Median PFS (investigator-assessed)Aumolertinib: 19.3 mo (95% CI: 17.8–20.8)

      Gefitinib: 9.9 mo (95% CI: 8.3–12.6)

      HR = 0.46 (95% CI: 0.36–0.60); p < 0.001
      Furmonertinib: 18.3 mo (95% CI: 15.2–20.8) vs.

      Gefitinib: 11.0 mo (95% CI: 9.7–12.4)

      HR = 0.51 (95% CI: 0.39–0.66); p < 0.0001
      Osimertinib: 16.5 mo (95% CI: 13.8–20.7)

      Gefitinib/erlotinib: 11.0 mo (95% CI: 9.5–12.6)

      HR = 0.54 (95% CI: 0.41–0.72); p < 0.0001
      Osimertinib: 18.9 mo (95% CI: 15.2–21.4)

      Gefitinib/erlotinib: 10.2 mo (95% CI: 9.6–11.1)

      HR = 0.46 (95% CI: 0.37–0.57); p < 0.001
      Median PFS (blinded independent review)Aumolertinib: 17.9 mo (95% CI: 15.1–20.5)

      Gefitinib: 9.7 mo (95% CI: 9.6–11.2)

      HR = 0.50 (95% CI: 0.39–0.64); p < 0.0001
      Furmonertinib: 20.8 mo (95% CI: 17.8–23.5)

      Gefitinib: 11.1 mo (95% CI: 9.7–12.5)

      HR = 0.44 (95% CI: 0.34–0.58); p < 0.0001
      NAOsimertinib: 17.7 mo (95% CI: 15.1–21.4)

      Gefitinib/erlotinib: 9.7 mo (95% CI: 8.5–11.0)

      HR = 0.45 (95% CI: 0.36–0.51); p < 0.001
      ORRAumolertinib: 73.8% (95% CI: 67.4–79.6)

      Gefitinib: 72.1% (95% CI: 65.6–78.0); p = 0.6939
      Furmonertinib: 89% (95% CI: 83–93)

      Gefitinib: 84% (95% CI: 78–89)

      OR = 1.50 (95% CI: 0.80–2.83; p = 0.21
      Osimertinib: 80% (95% CI: 73–86)

      Gefitinib/erlotinib: 75% (95% CI: 68–82)

      OR = 1.33 (0.78–2.28); p = 0.2918
      Osimertinib: 80% (95% CI: 75–85)

      Gefitinib/erlotinib: 76% (95% CI: 70–81)

      OR = 1.27 (95% CI: 0.85–1.90); p = 0.24
      Results (EGFR del19)
      Median PFSAumolertinib: 20.8 mo (95% CI: 18.1–20.9)

      Gefitinib: 12.3 mo (95% CI: 9.6–13.8)

      HR = 0.39 (95% CI: 0.28–0.54); p < 0.0001
      HR = 0.35 (95% CI: 0.23–0.53); p < 0.0001HR = 0.59 (95% CI: 0.41–0.85)Osimertinib: 21.4 mo (95% CI: 16.5–24.3)

      Gefitinib/erlotinib: 11.0 mo (95% CI: 9.7–12.6)

      HR = 0.43 (95% CI: 0.32–0.56); p < 0.001
      ORRNANANANA
      Results (EGFR L858R)
      Median PFSAumolertinib: 13.4 mo (95% CI: 7.3–18.0)

      Gefitinib: 8.3 mo (95% CI: 6.8–9.9)

      HR = 0.60 (95% CI: 0.40–0.89); p = 0.0102
      HR = 0.54 (95% CI: 0.37–0.77); p = 0.0006HR = 0.48 (95% CI: 0.31–0.74)Osimertinib: 14.4 mo (95% CI: 11.1–18.9)

      Gefitinib/erlotinib: 9.5 mo (95% CI: 8.1–11.0)

      HR = 0.51 (95% CI: 0.36–0.71); p < 0.001
      ORRNANANANA
      Results (brain mets present)
      Median PFSAumolertinib: 15.3 mo (95% CI: 10.8–20.8)

      Gefitinib: 8.2 mo (6.5–8.3)

      HR = 0.38 (0.24–0.60); p < 0.0001
      Furmonertinib: 18.0 mo (95% CI: 12.4–23.3)

      Gefitinib: 11.2 mo (95% CI: 8.2–15.1)

      HR = 0.52 (95% CI: 0.33–0.80); p = 0.0028
      HR = 0.68 (95% CI: 0.37–1.22)Osimertinib: 15.2 mo (95% CI: 12.1–21.4)

      Gefitinib/erlotinib: 9.6 mo (95% CI: 7.0–12.4)

      HR = 0.47 (95% CI: 0.30–0.74); p < 0.001
      ORRNANANAOsimertinib: 76% (95% CI: 62–86)

      Gefitinib/erlotinib: 86% (95% CI: 75–93)

      OR = 0.5 (95% CI: 0.2–1.3); p = 0.16
      Results (brain metastasis absent)
      Median PFSAumolertinib: 19.3 mo (17.8–NA)

      Gefitinib: 12.6 mo (9.6–14.0)

      HR = 0.51 (0.38–0.69); p < 0.0001
      Furmonertinib: 20.9 mo (95% CI: 18.0–23.6)

      Gefitinib: 11.1 mo (95% CI: 9.7–12.5)

      HR = 0·41 (0.29–0.58); p < 0.0001
      HR = 0.52 (95% CI: 0.38–0.72)Osimertinib: 19.1 mo (95% CI: 15.2–23.5)

      Gefitinib/erlotinib: 10.9 mo (95% CI: 9.6–12.3)

      HR = 0.46 (95% CI: 0.36–0.59); p < 0.0001
      ORRNANANAOsimertinib: 81% (95% CI: 75–86)

      Gefitinib/erlotinib: 73% (95% CI: 66–79)

      OR = 1.6 (95% CI: 1.0–2.5); p = 0.04
      Top 5 most common and unique treatment-related adverse events (all grades)
      Adverse eventsCPK elevation: 34.1%

      AST elevation: 28.0%

      ALT elevation: 27.6%

      Decrease WBC count: 20.6%

      Rash: 20.6%
      Elevated AST: 29%

      Diarrhea: 27%

      Elevated ALT: 26%

      Rash: 17%

      Decrease WBC count: 15%
      Rash and acne: 57%

      Diarrhea: 47%

      Paronychia: 38%

      Dry skin: 35%

      Stomatitis: 33%

      QT prolongation 14%-unique
      Rash and acne: 54%

      Diarrhea: 49%

      Dry skin: 33%

      Paronychia: 33%

      Stomatitis: 25%

      QT prolongation (10%)-treatment-emergent
      1G, first generation; 3G, third generation; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; CNS, central nervous system; CPK, creatinine phosphokinase; Del19, deletion exon 19; HR, hazard ratio; IQR, interquartile range; IRC, independent review committee; mets, metastasis; NA, not available; SOC, standard of care; TKI, tyrosine kinase inhibitor.
      Both trials compared well to the overall FLAURA population (HR by IRC = 0.45, 95% CI: 0.36–0.51, p < 0.001).
      • Soria J.C.
      • Ohe Y.
      • Vansteenkiste J.
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
      Among the subgroup of Asian patients enrolled in FLAURA, the statistical benefit of osimertinib remains (HR = 0.54, 95% CI: 0.41–0.72, p < 0.0001).
      • Cho B.C.
      • Chewaskulyong B.
      • Lee K.H.
      • et al.
      Osimertinib versus standard of care EGFR TKI as first-line treatment in patients with EGFRm advanced NSCLC: FLAURA Asian subset.
      Treatment-related QT prolongation occurred in 14% of the osimertinib-treated patients in FLAURA. The safety profile of furmonertinib is most closely similar to that of osimertinib.

      Path for Regulatory Approval of Asia’s 3G EGFR TKIs in the United States

      Two main pillars of drug development are developing novel first-in-class treatments and improving access to effective and affordable therapy but sometimes these two pillars conflict. By strict interpretation, innovation leads to monopoly because any subsequent development of the same class of drugs will carry the “me-too” derogatory label. As the only 3G EGFR TKI available for a long time, the initial price of osimertinib was prohibitively expensive, reflecting the speed in enrolling patients with EGFR T790M+ NSCLC into trials, such as 6 months, as recently in late 2019 in the rezivertinib trial.

      Shi Y, Wu S, Wang K, et al. Efficacy and safety of rezivertinib (BPI-7711) in patients with locally advanced or metastatic/recurrent EGFR T790M-mutated NSCLC: a phase IIb, multicenter, single-arm, open-label study [e-pub ahead of print]. J Thorac Oncol. https://doi.org/10.1016/j.jtho.2022.08.015, accessed September 20, 2022.

      The U.S. Food and Drug Administration (FDA) and the European Medicines Agency have published guidelines on considerations of foreign data from a regulatory perspective. The ICH-E5 guideline, published in 1998, provides a framework for evaluating a new product’s sensitivity to ethnic factors and the need for a bridging study. The goal of the ICH-E5 framework is to avoid repeating clinical trials, which may be costly and delay access to effective medications.
      • Gupta S.K.
      Implications of ICH-E5: assessment of drug’s sensitivity to ethnic factors and necessity of a bridging study for global drug development.
      ,
      European Medicines Agency
      ICH topic E 5 (R1): ethnic factors in the acceptability of foreign clinical data.
      Both agencies require validation of compliance to good clinical practices (GCP) and request for GCP inspection on clinical trial sites where a marketing-authorization application has been submitted. The FDA has additional criteria (21 CFR 314.106) for the approval of a drug based only on foreign data, which are as follows: (1) foreign data are applicable to the U.S. population and U.S. medical practice; (2) studies are performed by investigators of recognized competence; and (3) FDA validation of trial data through on-site inspections or other appropriate means.
      Some will argue that EGFR+ NSCLC is a unifying molecular subtype of NSCLC that responds to EGFR TKIs regardless of ethnicity of the patient. Nevertheless, the process to gain approval is arduous. Take the “re-introduction” of gefitinib into the United States as first-line treatment of patients with EGFR+ NSCLC as an example. FDA approval was obtained
      • Kazandjian D.
      • Blumenthal G.M.
      • Yuan W.
      • He K.
      • Keegan P.
      • Pazdur R.
      FDA approval of gefitinib for the treatment of patients with metastatic EGFR mutation-positive non-small cell lung cancer.
      after a phase 4 single-arm study conducted exclusively in European patients on the efficacy and safety of gefitinib in EGFR+ NSCLC (IFUM)
      • Douillard J.Y.
      • Ostoros G.
      • Cobo M.
      • et al.
      First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study.
      in addition to a retrospective, blinded, IRC-assessed PFS of the subgroup of patients with EGFR+ NSCLC (retrospectively identified) who received gefitinib versus carboplatin/paclitaxel in the landmark IPASS trial.
      • Wu Y.L.
      • Saijo N.
      • Thongprasert S.
      • et al.
      Efficacy according to blind independent central review: post-hoc analyses from the phase III, randomized, multicenter, IPASS study of first-line gefitinib versus carboplatin/paclitaxel in Asian patients with EGFR mutation-positive advanced NSCLC.
      The recent decision by the FDA in rejecting the application of sintilimab, studied in the phase 3 ORIENT-11 trial
      • Yang Y.
      • Wang Z.
      • Fang J.
      • et al.
      Efficacy and safety of sintilimab plus pemetrexed and platinum as first-line treatment for locally advanced or metastatic nonsquamous NSCLC: a randomized, double-blind, phase 3 study (oncology pRogram by InnovENT anti-PD-1-11).
      ,
      • Yang Y.
      • Sun J.
      • Wang Z.
      • et al.
      Updated overall survival data and predictive biomarkers of sintilimab plus pemetrexed and platinum as first-line treatment for locally advanced or metastatic nonsquamous NSCLC in the phase 3 ORIENT-11 study.
      in the People’s Republic of China, offers insight into the challenges that Asia’s 3G EGFR TKIs will face in getting regulatory approval in Western countries.
      Food and Drug Administration
      FDA Briefing Document Oncologic Drugs Advisory Committee Meeting: Sintilimab Innovent Biologics (Suzhou) Co., Ltd.
      ,
      Food and Drug Administration
      Sintilimab for locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC).
      Despite vigorous arguments from the supporters of ORIENT-11,
      • Liu S.V.
      • Nagasaka M.
      • Stefaniak V.
      • et al.
      The applicability of the results in the Asian population of ORIENT-11 to a western population according to the ICH-E5 framework.
      ,
      • Nagasaka M.
      • Molife C.
      • Cui Z.L.
      • et al.
      Generalizability of ORIENT-11 trial results to a US standard-of-care cohort with advanced non-small-cell lung cancer.
      the rejection reasons highlighted by the FDA were single-country study (does not represent the diversity of the U.S. population, unknown pharmacokinetics of sintilimab in non-Chinese patients), inappropriate control arm (platinum-chemotherapy alone; although KEYNOTE-189 was just approved in the People’s Republic of China and carried a huge cost for patients), suboptimal choice of study end points (PFS rather than overall survival for prospective statistical calculation and follow-up), nonadherence to GCP, lack of FDA advance consultation and oversight, and limited clinical inspections due to Covid-19 pandemic.
      Food and Drug Administration
      FDA Briefing Document Oncologic Drugs Advisory Committee Meeting: Sintilimab Innovent Biologics (Suzhou) Co., Ltd.
      ,
      Food and Drug Administration
      Sintilimab for locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC).
      The two most promising 3G EGFR TKIs, aumolertinib and furmonertinib, with their well-conducted AENEAS and FURLONG phase 3 trials, respectively, lack all the criteria set out by the U.S. FDA ORIENT-11 decisions (only conducted in the People’s Republic of China, inappropriate control arm of 1G EGFR TKI, PFS as primary end point). It remains to be seen whether these two 3G EGFR TKIs will be able to reach the global stage.

      Aggarwal C, Gyawali B. Aumolertinib in EGFR-mutant lung cancer: will the promise of cost disruption ease access? [e-pub ahead of print]. J Clin Oncol. https://doi.org/10.1200/JCO.22.00903, accessed September 20, 2022.

      In addition, the unique side effects of CPK elevation in aumolertinib will likely be needed to be investigated in non-Asian patients minimally ala IFUM single-arm phase 2 design.
      • Douillard J.Y.
      • Ostoros G.
      • Cobo M.
      • et al.
      First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study.
      Many of the FDA’s concerns on study designs on AENEAS and FURLONG also apply to the frontline trials involving Asia’s 3G EGFR TKIs. Additionally, befotertinib is compared with icotinib (Table 2), an 1G EGFR TKI that is not approved outside the People’s Republic of China, and thus the regulatory path for befotertinib will face additional challenge. Even in the LASER301 study (NCT04248829), which addresses some of the FDA concerns by involving multiregional sites, the lack of participation of U.S. patients likely dims its chance of approval in the United States as monotherapy for frontline treatment of advanced EGFR+ NSCLC. Lazertinib alone or in combination with amivantamab is undergoing first-line (MARIPOSA-1, NCT04487080) and second-line (lazertinib + amivantamab + chemotherapy; MARIPOSA-2, NCT04988295) treatment of advanced EGFR+ NSCLC, thus having two additional “shots on goal” for regulatory approval albeit at a later date.
      • Nagasaka M.
      • Ou S.I.
      ORIENT-31 as the sakigake “charging samurai” born of IMpower150 but will MARIPOSA-2 IMPRESS in the “Meiji modernization” of post-3G EGFR TKI progression?.

      Concluding Remarks

      In summary, of the four 3G EGFR TKIs that formed the basis of this editorial, SH-1028 and rezivertinib seem to have both good clinical efficacy and safety and once-daily dosing convenience. The dosing regimens of limertinib and befotertinib will likely need to be optimized in non-Chinese/non-Asian patients if they are going to be developed outside the People’s Republic of China given the high incidence of diarrhea (limertinib) and headache and thrombocytopenia (befotertinib). Furthermore, twice-daily dosing (limertinib) or step-up dosing (befotertinib) will limit their adaptability globally in face of first-mover effects of aumolertinib furmonertinib and lazertinib.
      Nevertheless, aumolertinib and furmonertinib are the two front-running 3G EGFR TKIs with published clinical efficacy against 1G EGFR TKIs with acceptable adverse events. We eagerly await the disposition of aumolertinib’s application to the United Kingdom on the basis of the AEANAS trial,
      EQRx
      EQRx announces acceptance of marketing authorization application by the UK's medicines and healthcare products regulatory agency for aumolertinib in EGFR-mutated non-small cell lung cancer.
      the results of which either set the precedence for approvals of 3G EGFR TKIs outside of the People’s Republic of China or remain them a “bridge too far over troubled waters.”
      • Singh H.
      • Pazdur R.
      Importing oncology trials from China: a bridge over troubled waters?.
      ,
      • Benjamin D.J.
      • Prasad V.
      • Lythgoe M.P.
      FDA decisions on new oncological drugs.

      CRediT Authorship Contribution Statement

      Sally C. M. Lau, Sai-Hong Ignatius Ou: Conceptualization, Data curation, Validation, Writing—original draft, Writing—review and editing.

      Acknowledgments

      The authors thank Dr. Michael Greco of Beta-Pharma (Princeton, NJ) for generating the structures for Figure 1.

      References

        • Midha A.
        • Dearden S.
        • McCormack R.
        EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII).
        Am J Cancer Res. 2015; 5: 2892-2911
        • Nagasaka M.
        • Zhu V.W.
        • Lim S.M.
        • Greco M.
        • Wu F.
        • Ou S.I.
        Beyond osimertinib: the development of third-generation EGFR tyrosine kinase inhibitors for advanced EGFR+ NSCLC.
        J Thorac Oncol. 2021; 16: 740-763
        • Mok T.S.
        • Wu Y.-L.
        • Ahn M.-J.
        • et al.
        Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.
        N Engl J Med. 2017; 376: 629-640
        • AstraZeneca
        Tagrisso approved in China as a 1st-line treatment for EGFR-mutated non-small cell lung cancer.
        (Accessed September 20, 2022.)
        • Camidge D.R.
        Icotinib: kick-starting the Chinese anticancer drug industry.
        Lancet Oncol. 2013; 14: 913-914
        • Adjei A.A.
        Tackling the high cost of oncology drugs.
        J Thorac Oncol. 2021; 16: 1774-1777
        • Shi Y.
        • Li B.
        • Wu L.
        • et al.
        Efficacy and safety of limertinib (ASK120067) in patients with locally advanced or metastatic EGFR T790M mutated non-small cell lung cancer: a multicenter, single-arm, phase 2b study [e-pub ahead of print]. J Thorac Oncol.
        (accessed August 15, 2022)
        • Shun L.
        • Zhang Y.
        • Zhang G.
        • et al.
        Efficacy and safety of befotertinib (D-0316) in patients with EGFR T790M mutated non-small cell lung cancer that had progressed after prior EGFR TKI therapy: a phase 2, multicenter, single-arm, open-label study [e-pub ahead of print]. J Thorac Oncol.
        (accessed August 15, 2022)
        • Xiong A.
        • Ren S.
        • Liu H.
        • et al.
        Efficacy and safety of SH-1028 in patients with EGFR T790M positive non-small-cell lung cancer: a multicenter, single-arm, open-label, phase 2 trial [e-pub ahead of print]. J Thorac Oncol.
        (accessed August 15, 2022)
      1. Shi Y, Wu S, Wang K, et al. Efficacy and safety of rezivertinib (BPI-7711) in patients with locally advanced or metastatic/recurrent EGFR T790M-mutated NSCLC: a phase IIb, multicenter, single-arm, open-label study [e-pub ahead of print]. J Thorac Oncol. https://doi.org/10.1016/j.jtho.2022.08.015, accessed September 20, 2022.

        • Ahn M.J.
        • Tsai C.M.
        • Shepherd F.A.
        • et al.
        Osimertinib in patients with T790M mutation-positive, advanced non-small cell lung cancer: long-term follow-up from a pooled analysis of 2 phase 2 studies.
        Cancer. 2019; 125: 892-901
        • Zhou C.
        • Wang M.
        • Cheng Y.
        • et al.
        AURA17 study of osimertinib in Asia-Pacific patients (pts) with EGFR T790Mpositive advanced non-small cell lung cancer (NSCLC): updated phase II results including overall survival (OS).
        Ann Oncol. 2018; 29: IX157
        • Shi Y.
        • Hu X.
        • Zhang S.
        • et al.
        Efficacy, safety, and genetic analysis of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small-cell lung cancer: a phase 2b, multicentre, single-arm, open-label study.
        Lancet Respir Med. 2021; 9: 829-839
        • Lu S.
        • Wang Q.
        • Zhang G.
        • et al.
        Efficacy of aumolertinib (HS-10296) in patients with advanced EGFR T790M+ NSCLC: updated post-national medical products administration approval results from the APOLLO registrational trial.
        J Thorac Oncol. 2022; 17: 411-422
        • Cho B.C.
        • Han J.Y.
        • Kim S.W.
        • et al.
        A phase 1/2 study of lazertinib 240 mg in patients with advanced EGFR T790M-positive NSCLC after previous EGFR tyrosine kinase inhibitors.
        J Thorac Oncol. 2022; 17: 558-567
      2. Lu S, Dong X, Jian H, et al. AENEAS: a randomized phase III trial of aumolertinib versus gefitinib as first-line therapy for locally advanced or metastatic non-small-cell lung cancer with EGFR exon 19 deletion or L858R mutations [e-pub ahead of print]. J Clin Oncol. https://doi.org/10.1200/JCO.21.02641, accessed September 20, 2022.

      3. Shi Y, Chen G, Wang X, et al. Furmonertinib (AST2818) versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (FURLONG): a multicentre, double-blind, randomised phase 3 study [e-pub ahead of print]. Lancet Respir Med. https://doi.org/10.1016/S2213-2600(22)00168-0, accessed September 20, 2022.

        • Soria J.C.
        • Ohe Y.
        • Vansteenkiste J.
        • et al.
        Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
        N Engl J Med. 2018; 378: 113-125
        • Ramalingam S.S.
        • Vansteenkiste J.
        • Planchard D.
        • et al.
        Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC.
        N Engl J Med. 2020; 382: 41-50
        • Cho B.C.
        • Chewaskulyong B.
        • Lee K.H.
        • et al.
        Osimertinib versus standard of care EGFR TKI as first-line treatment in patients with EGFRm advanced NSCLC: FLAURA Asian subset.
        J Thorac Oncol. 2019; 14: 99-106
        • Shi Y.
        • Zhao Y.
        • Yang S.
        • et al.
        Safety, efficacy, and pharmacokinetics of rezivertinib (BPI-7711) in patients with advanced NSCLC with EGFR T790M mutation: a phase 1 dose-escalation and dose-expansion study.
        J Thorac Oncol. 2022; 17: 708-717
        • Papadimitrakopoulou V.A.
        • Han J.Y.
        • Ahn M.J.
        • et al.
        Epidermal growth factor receptor mutation analysis in tissue and plasma from the AURA3 trial: osimertinib versus platinum-pemetrexed for T790M mutation-positive advanced non-small cell lung cancer.
        Cancer. 2020; 126: 373-380
        • Wang F.
        • Adjei A.A.
        Does the lung cancer field need another third-generation EGFR tyrosine kinase inhibitor?.
        J Thorac Oncol. 2020; 15: 881-883
        • Wang F.
        • Zhou Q.
        The challenges of third-generation EGFR tyrosine kinase inhibitors in the therapy of advanced NSCLC.
        J Thorac Oncol. 2022; 17: 481-486
        • Gupta S.K.
        Implications of ICH-E5: assessment of drug’s sensitivity to ethnic factors and necessity of a bridging study for global drug development.
        Perspect Clin Res. 2011; 2: 121-123
        • European Medicines Agency
        ICH topic E 5 (R1): ethnic factors in the acceptability of foreign clinical data.
        • Kazandjian D.
        • Blumenthal G.M.
        • Yuan W.
        • He K.
        • Keegan P.
        • Pazdur R.
        FDA approval of gefitinib for the treatment of patients with metastatic EGFR mutation-positive non-small cell lung cancer.
        Clin Cancer Res. 2016; 22: 1307-1312
        • Douillard J.Y.
        • Ostoros G.
        • Cobo M.
        • et al.
        First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study.
        Br J Cancer. 2014; 110: 55-62
        • Wu Y.L.
        • Saijo N.
        • Thongprasert S.
        • et al.
        Efficacy according to blind independent central review: post-hoc analyses from the phase III, randomized, multicenter, IPASS study of first-line gefitinib versus carboplatin/paclitaxel in Asian patients with EGFR mutation-positive advanced NSCLC.
        Lung Cancer. 2017; 104: 119-125
        • Yang Y.
        • Wang Z.
        • Fang J.
        • et al.
        Efficacy and safety of sintilimab plus pemetrexed and platinum as first-line treatment for locally advanced or metastatic nonsquamous NSCLC: a randomized, double-blind, phase 3 study (oncology pRogram by InnovENT anti-PD-1-11).
        J Thorac Oncol. 2020; 15: 1636-1646
        • Yang Y.
        • Sun J.
        • Wang Z.
        • et al.
        Updated overall survival data and predictive biomarkers of sintilimab plus pemetrexed and platinum as first-line treatment for locally advanced or metastatic nonsquamous NSCLC in the phase 3 ORIENT-11 study.
        J Thorac Oncol. 2021; 16: 2109-2120
        • Food and Drug Administration
        FDA Briefing Document Oncologic Drugs Advisory Committee Meeting: Sintilimab Innovent Biologics (Suzhou) Co., Ltd.
        • Food and Drug Administration
        Sintilimab for locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC).
        • Liu S.V.
        • Nagasaka M.
        • Stefaniak V.
        • et al.
        The applicability of the results in the Asian population of ORIENT-11 to a western population according to the ICH-E5 framework.
        Front Oncol. 2022; 12859892
        • Nagasaka M.
        • Molife C.
        • Cui Z.L.
        • et al.
        Generalizability of ORIENT-11 trial results to a US standard-of-care cohort with advanced non-small-cell lung cancer.
        Future Oncol. 2022; 18: 1963-1977
      4. Aggarwal C, Gyawali B. Aumolertinib in EGFR-mutant lung cancer: will the promise of cost disruption ease access? [e-pub ahead of print]. J Clin Oncol. https://doi.org/10.1200/JCO.22.00903, accessed September 20, 2022.

        • Nagasaka M.
        • Ou S.I.
        ORIENT-31 as the sakigake “charging samurai” born of IMpower150 but will MARIPOSA-2 IMPRESS in the “Meiji modernization” of post-3G EGFR TKI progression?.
        Lung Cancer (Auckl). 2022; 13: 13-21
        • EQRx
        EQRx announces acceptance of marketing authorization application by the UK's medicines and healthcare products regulatory agency for aumolertinib in EGFR-mutated non-small cell lung cancer.
        (Accessed September 20, 2022)
        • Singh H.
        • Pazdur R.
        Importing oncology trials from China: a bridge over troubled waters?.
        Lancet Oncol. 2022; 23: 323-325
        • Benjamin D.J.
        • Prasad V.
        • Lythgoe M.P.
        FDA decisions on new oncological drugs.
        Lancet Oncol. 2022; 23: 585-586

      Linked Article