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West asco clin mgmt acquired resistance tk is

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West asco clin mgmt acquired resistance tk is

  1. 1. Clinical Perspective on Acquired Resistance:Defining and Overcoming BarriersHoward (Jack) West, MDSwedish Cancer InstituteSeattle, WAASCO Annual MeetingChicago, ILJune 1, 2013
  2. 2. Acquired Resistance to Targeted Therapies InNSCLC: Management in the Clinic Today• Detectable vs. clinically significant progression?• Role of local therapy?• Continue targeted therapy?• Value to re-challenge?• Repeat biopsy?Outline of key questions
  3. 3. Acquired Resistance to Targeted Therapy:Heterogeneous PatternsDiverse molecular mechanisms of resistance diverse clinical patterns of progression• Single focus of progression• Slow, minimal multifocal progression• Rapid, more diffuse progression
  4. 4. Does Detectable Progression Require aTreatment Change?NOT necessarily clinically significant progressionDiseaseburdenTime
  5. 5. Is it clinically significant progression?Questionable/dubious indicatorsMild increase in metabolic activity on PETRising serum tumor markerSlow, slight increase in tumor size(1-2 small new nodules vs. otherwiseexcellent disease control?)
  6. 6. Continued treatment beyond progression,Dana Farber Experience• 42 EGFR mutn-pos pts s/p 1st line erlotinib on one of 3clinical trials• 45% continued without significant progression > 3 months• 21% required no further treatment change for > 12 monthsOxnard, ASCO 2012, A#7524
  7. 7. If significant progression, is it isolatedor more diffuse?Is “oligoprogression” analogous tooligometastatic/precocious metastatic disease?Perhaps especially for CNS disease• Poor CNS penetration of both EGFR TKIs and crizotinib,so brain mets may not represent resistance to drug(Bronischer CCR, 2007; Costa JCO 2011)• T790M seen in 60% of progressing lesions in acquiredresistance, but only 10% of lesions from CNS progression(Hata, ASCO 2012, A#7528)
  8. 8. Local Therapy in Acquired Resistance:University of Colorado Experience• 65 pts (38 ALK+, 27 EGFR mut’n+) of whom 51 (28 ALK, 23 EGFR)progressed• 25 (49%) with CNS (no LMC) or <4 extracranial sites of progressionWeickhardt, J Thorac Oncol 2013
  9. 9. Chen,Oncologist 2012Variability of Molecular Markers Over Timeand Across Disease Sites• Heterogeneity ofmolecular changes acrosslesions• Acquired resistance maybe anatomically isolated
  10. 10. Local Therapy in Acquired Resistance:Extracranial Oligoprogression• 18/184 pts  local therapy for extracranial PD(CNS PD excluded)Yu, J Thorac Oncol 2013• Median time to newsystemic Rx: 22 months
  11. 11. Rapid acceleration of PD  hospitalization and/or death afterdiscontinuation of EGFR seen in up to ~1/4 of pts in MSKCC series(Chaft, Clin Cancer Res, 2011)Also reported after discontinuation of crizotinib after acquiredresistance in ALK-positive NSCLC (Pop, J Thorac Oncol, 2012)Last day of TKI Off EGFR TKI Resumed TKIDay 0 Day 21 Day 42Rapid Progression with Discontinuation ofEGFR TKI after Prolonged PFS
  12. 12. For Cancers with a Known Driver Mutation, ContinuingInhibition of that Target is Beneficial after Progression• Progression of CML on imatinib  increase dose, or dasatinib, ornilotinib lead to consistent response• Solid tumor example: HER2+ breast cancervon Minckwitz, JCO 2009
  13. 13. Treatment Options after AcquiredResistance to EGFR (or other) TKIOxnard, Clin Cancer Res, 2011
  14. 14. Chemo/Erlotinib vs. Chemo Alone atProgression after Acquired Resistance• N = 78 retrospective review ofoutcomes– chemo alone (N = 44) or– chemo/erlotinib (N = 34)• RR 18% (chemo) vs. 41% withchemo/erlotinib)• No differences in PFS or OS betweenthese two strategiesGoldberg, ASCO 2012, A#7524
  15. 15. Chemo with Concurrent TKI• Studies in unselected or clinically selected populations show nobenefit but no signal of increased harm• Combinations of chemo and TKIs are certainly feasible• Little prospective study in setting of acquired resistance yet• ph II trial of pem/EGFR TKI as 3rd line (Yoshimura, JTO 2013)• N = 27; RR 26%, DCR 78%, med PFS 7.0 mo, med OS 11.4 mo• Unclear if they are significantly more favorable thanchemo alone in acquired resistance
  16. 16. Chemotherapy +/- Ongoing EGFR TKI forAcquired ResistancePrimary endpoint: progression-free survivalActivating EGFR mutationProgression on gefitinibNo prior chemotherapyN = 250RANDCisplatin/PemetrexedIMPRESS TRIALPI: Tony Mok & Jean-Charles SoriaCisplatin/Pemetrexed+ ongoing gefitinib
  17. 17. Chemotherapy +/- Ongoing EGFR TKI forAcquired Resistance, with RetreatmentPrimary endpoint: progression-free survivalPI: Leora Horn (Vanderbilt)Advanced NSCLCActivating EGFR mutationResp to EGFR TKI>4 moNo prior chemotherapyPS 0/1N = 120RANDCis or Carbo/Pemetrexed+ ongoing erlotinibStratification by:EGFR mut’n exon 19 vs. exon 21Time to progression on EGFR TKI <1 yr vs. >1 yrPS 0 vs. 1Cis or Carbo/PemetrexedErlotinib re-treatment
  18. 18. Chemotherapy +/- Ongoing Crizotinib forAcquired Resistance in ALK-Positive NSCLCCo-primary endpoints:Progression-free survivalResponse rate, pemetrexed aloneALK rearrangementProgression on crizotinibafter response or SD>3 moNo prior pemetrexedN = 114RANDPemetrexed alonePI: D. Ross CamidgePemetrexed + ongoing+ crizotinibSWOG 1300 (in development)
  19. 19. Chemo Without TKI Can BeFollowed by Re-treatmentOxnard, Clin Cancer Res, 2011
  20. 20. EGFR TKI Re-treatment after AcquiredResistance: DFCI/MGH Experience• Retrospective, 24 pts (over 9.5 yrs)with activating EGFR mutation after ARto gefitinib (30%) or erlotinib (70%)• RR 4%, SD 63%• Median interval off EGFR TKI 5 mo(range 2-46 mo)• Greater benefit w/longer interval ofEGFR TKI (PFS 4.4 vs. 1.9 mo for 6mo interval off EGFR TKI)Heon, ASCO 2012, A#7525
  21. 21. MISSION Trial of Sorafenib vs. Placebo:PFS based on EGFR mutation statusBiomarker*treatment interaction analysis: p-value=0.015Patients with EGFR mut (in tumor orplasma)• Sorafenib N=44; Placebo N=45• HR=0.27 (95% CI 0.16,0.46)• P-value<0.001• Sorafenib median PFS= 2.7 mo (83d)• Placebo median PFS= 1.4 mo (42d)Patients with EGFR wild type• Sorafenib N=122; Placebo N=136• HR=0.62 (95% CI 0.48,0.82)• P-value<0.001• Sorafenib median PFS= 2.7 mo (82d)• Placebo median PFS= 1.5 mo (46d)Mok, ESMO 2012
  22. 22. MISSION Trial of Sorafenib vs. Placebo:OS based on EGFR mutation statusPatients with EGFR mut (in tumor or plasma)• Sorafenib N=44; Placebo N=45• HR=0.48 (95% CI 0.3,0.76)• P-value=0.002• Sorafenib median OS= 13.9 mo (423d)• Placebo median OS= 6.5 mo (197d)Patients with EGFR wild type• Sorafenib N=122; Placebo N=136• HR=0.92 (95% CI 0.7,1.21)• P-value=0.559• Sorafenib median OS= 8.3 mo (253d)• Placebo median OS= 8.4 mo (256d)Biomarker*treatment interaction analysis: p-value=0.023Mok, ESMO 2012
  23. 23. Are Repeat Biopsies Mandatory,Desirable, or Neither?Yu, Clin Cancer Res, 2013Not standard of care, relatively low probability of beingimmediately actionable, but repeat biopsies are likely to drive ourunderstanding and future treatments in this setting.• SCLC in 3-15%• Potential insight re: prognosis(+/- value of ongoing TKI?)• Otherwise, uncommon to findactionable result with currentapproved agentsN=155
  24. 24. Conclusions on Clinical Managementof Acquired Resistance (1)• Clinical as well as molecular heterogeneity• No clear evidence-based best approach defined yet• Not all progression merits change in therapy• “Oligoprogressive” acquired resistance– Consider local Rx and continue targeted therapy– CNS as pharmacodynamic issue, not acquired resistance• Diffuse progressive disease– Option of continuing TKI with concurrent chemo to avoid“flare”, treat different cell populations– Option of switching to chemo only, potentially followed byre-treatment
  25. 25. Conclusions on Clinical Managementof Acquired Resistance (2)• Prospective randomized trials are needed– Very real potential for bias in retrospective analyses• Trials of novel agents or combinations– Very attractive option for prospectively identified specialpopulation – consider clinical trials• Role for repeat biopsy?– Uncommon to have actionable result today– Very likely to increase our understanding of the field andidentify future treatment options

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