Trastuzumab duocarmazine in HER2+ metastatic breast cancer – TULIP trial results: Philippe Aftimos, ESMO 2023

The final results of the phase 3, TULIP trial (NCT03262935), which compared trastuzumab duocarmazine (T-Duo) with physician’s choice of therapy in previously treated HER2-positive metastatic breast cancer, were presented at ESMO 2023. 

Dr. Philippe Aftimos, the study investigator from the Institute Jules Bordet in Belgium, presented the results at the conference and then discussed them with us at touchONCOLOGY.

Questions

1. What are the current unmet needs in the treatment of HER2-positive metastatic breast cancer (MBC)? (0.20)
2. What is trastuzumab duocarmazine (T-Duo) and what is its mechanism of action? (1:33)
3. What were the aims, design, and eligibility criteria of the TULIP study? (1:58)
4. What were the study findings in terms of the primary and secondary endpoints? (2:53)
5. What were the study findings in terms of safety? (3:48)
6. Are there any questions that remain unanswered and what will be the next steps in the clinical development of T-Duo? (4:36)

Disclosures: Philippe Aftimos has acted as a consultant for Amcure, Amgen, Boehringer Ingelheim, Daiichi Sankyo, Deloitte, Eli Lilly,Gilead, Incyte, Macrogenics, Menarini,Novartis, Synthon and Radius, and recieved grant/research support from Roche.

Support: Interview and filming supported by Touch Medical Media Ltd. Interview conducted by Gina Furnival

Filmed in coverage of the ESMO 2023

Click here for more content on breast cancer & for further ESMO 2023 highlights visit here.

Transcript

I am Phillip Aftimos. I’m a medical oncologist working in breast oncology and precision medicine and I’m also the Head of the Clinical Trials unit in a comprehensive cancer center in Brussels called Institute Jules Bordet, affiliated with the Universté Libre de Brussels.

Q1. What are the current unmet needs in the treatment of HER2-positive metastatic breast cancer (MBC)? (0.20)

HER2-positive  metastatic  breast  cancer  has  seen  a  lot  of  advances  in  the  last  few  years.  So  just  to  set  the  scene,  HER2-positive  breast  cancer  is  20  percent  of  full  breast  cancers.  This  was  a  very  tough  cancer  to  treat  because  of  aggressivity,  but  we  started  therapies  that  are  aimed  at  the  HER2  overexpression  and  the  HER2  amplification,  and  we  improved  a  lot,  and  actually,  the  overall  survival  of  patients  has  improved  a  lot.  There  are  still  some  unmet  needs.  There  is  now  an  antibody-drug  conjugate  called  trastuzumab  deruxtecan,  which  is  highly  potent  and  approved  in  the  metastatic  setting.  However,  however,  we  have  very  little  data  on  treatment  after  trastuzumab  deruxtecan  when  patients  have  disease  progression.  And  another  area  of  unmet  need,  are  the  central  nervous  system  metastasis.  We  know  that  this  type  of  disease  has  a  propensity  to  go  into  the  brain  and  the  meninges,  and,  the  last  few  years  I  have  seen  some  drugs  whose  activity  there,  such  as  tucatinib,  but  this  is  still  I  believe  an  area  of  need.

Q2. What is trastuzumab duocarmazine (T-Duo) and what is its mechanism of action? (1:33)

It’s  actually  a  third  generation,  antibody  drug-conjugate  targeting  the  HER2  receptor.  It  has  a  cleavable  linker  and  the  payload  is  duocarmycin,  which  is  a  minor  group  binder  activating  agent  with  a  drug-antibody  ratio  between  2.4  and  2.8.

Q3. What were the aims, design, and eligibility criteria of the TULIP study? (1:58)

This  is  a  phase  3  study,  that  randomized  patients  2:1  to  T-Duo  versus  treatment  of  physician’s  choice,  which  was  chemotherapy  in  combination  with  an  anti-HER2  therapy.  So  this  could  have  been  eribulin  plus  trastuzumab,  capecitabine  plus  trastuzumab,  lapatinib  plus  capecitabine,  vinorelbine  plus  trastuzumab.

So  patients,  should  have  had  advanced  breast  cancer  that  was  HER2-positive.  This  could  have  been  metastatic  breast  cancer  or  locally  advanced,  not  amenable  to  surgical  resection.  Four  hundred  and  thirty  seven  patients  were  randomized,  and,  they  should  have  received  two  prior  lines  of  therapy  for  metastatic  disease,  or  should  have  received,  TDM1.

Patients  with  stable  brain  metastases  were  allowed  in  the  study.

Q4. What were the study findings in terms of the primary and secondary endpoints? (2:53)

The  primary  endpoint  was  presented  at  ESMO  2021,  so  this  was  centrally  assessed  progression  free  survival  and  there  the  study  met  its  objective,  with  a  PFS  of  7  months  for  the  investigational  arm  of  T-Duo  versus  4.9  months  in  the  treatment  of  physician’s  choice  and  the  hazard  ratio  was  0.36.

Together  endpoints  included  investigator  assessed  PFS,  overall  survival  response  rate,  adverse  events  and  the  quality  of  life.  For  the  secondary  endpoint,  there  was  no  improvement,  statistically  significant  improvement  in  overall  survival.  Numerically  there  was  an  improvement  with  T-Duo  from  21  months  versus  19.5  months,  but  again,  as  I  said,  this  was  not  statistically  significant.

Q5. What were the study findings in terms of safety? (3:48)

T-Duo,  like  other  antibody-drug  conjugates,  actually,  has,  mainly  ophthalmological  adverse  events.  So  either  keratitis  or  conjunctivitis.  So  those  were  the  most  prevalent  adverse  events  in  the  investigational  arm.  So  it  was  as  high  as  78  percent,  including  28  percent  that  were  Grade  3,  and  about  21  percent  of  patients  had  treatment  discontinuation,  and  about  23  percent  had  dose  modifications.

Like,  also,  like  other  antibody-drug  conjugates,  there  was  some  interstitial  lung  disease  (ILD).  So  the  rate,  the  prevalence  was  7.6  percent.

Grade  3  was  2.4  percent,  and,  about  5  percent  of  patients  discontinued  because  of  ILD.

Q6. Are there any questions that remain unanswered and what will be the next steps in the clinical development of T-Duo? (4:36)

Well  I  believe  the  study,  was  performed,  whilst  trastuzumab  deruxtecan  was  not  yet  the  standard  of  care.

So  we  still,  we  still  have  the  question  of  what  to  do  post-trastuzumab  deruxtecan  currently.  Approved  as  early  as  the  second-line  or  even  first-line  in  patients  that  relapse  quickly  after  trastuzumab  and  pertuzumab.

For  me,  the  logical  step  would  be  to  evaluate  efficacy  post  T-DXd  but  also,  do  a  larger  study  in  the  HER2-low  subset  because  this  is  also  now  an  area  of  investigational  anti-HER2  therapies,  but  you  also  have  an  approved  drug  that  is,  again  trastuzumab  deruxtecan.

Subtitles and transcript are autogenerated.