Clinical Perspective on Acquired Resistance: Defining and Overcoming Barriers

Howard (Jack) West, MDSwedish Cancer Institute

Seattle, WA

ASCO Annual MeetingChicago, IL

June 1, 2013

Acquired Resistance to Targeted Therapies In NSCLC: 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

Acquired Resistance to Targeted Therapy: Heterogeneous Patterns

Diverse molecular mechanisms of resistance diverse clinical patterns of progression

•Single focus of progression •Slow, minimal multifocal progression

•Rapid, more diffuse progression

Does Detectable Progression Require a Treatment Change?

NOT necessarily clinically significant progression

Disease burden

Time

Is it clinically significant progression?

Questionable/dubious indicators

Mild increase in metabolic activity on PET

Rising serum tumor marker

Slow, slight increase in tumor size

(1-2 small new nodules vs. otherwise excellent disease control?)

Continued treatment beyond progression, Dana Farber Experience

• 42 EGFR mutn-pos pts s/p 1st line erlotinib on one of 3 clinical trials

• 45% continued without significant progression > 3 months• 21% required no further treatment change for > 12 months

Oxnard, ASCO 2012, A#7524

If significant progression, is it isolatedor more diffuse?

Is “oligoprogression” analogous to oligometastatic/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 acquired resistance, but only 10% of lesions from CNS progression (Hata, ASCO 2012, A#7528)

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 progression

Weickhardt, J Thorac Oncol 2013

Chen, Oncologist 2012

Variability of Molecular Markers Over Timeand Across Disease Sites

• Heterogeneity of molecular changes across lesions

• Acquired resistance may be anatomically isolated

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 new systemic Rx: 22 months

Rapid acceleration of PD hospitalization and/or death after discontinuation 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 acquired resistance in ALK-positive NSCLC (Pop, J Thorac Oncol, 2012)

Last day of TKI Off EGFR TKI Resumed TKI

Day 0 Day 21 Day 42

Rapid Progression with Discontinuation of EGFR TKI after Prolonged PFS

For Cancers with a Known Driver Mutation, ContinuingInhibition of that Target is Beneficial after Progression

• Progression of CML on imatinib increase dose, or dasatinib, or nilotinib lead to consistent response

• Solid tumor example: HER2+ breast cancer

von Minckwitz, JCO 2009

Treatment Options after Acquired Resistance to EGFR (or other) TKI

Oxnard, Clin Cancer Res, 2011

Chemo/Erlotinib vs. Chemo Alone at Progression after Acquired Resistance

• N = 78 retrospective review of outcomes – chemo alone (N = 44) or– chemo/erlotinib (N = 34)

• RR 18% (chemo) vs. 41% with chemo/erlotinib)

• No differences in PFS or OS between these two strategies

Goldberg, ASCO 2012, A#7524

Chemo with Concurrent TKI

• Studies in unselected or clinically selected populations show no benefit 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 than chemo alone in acquired resistance

Chemotherapy +/- Ongoing EGFR TKI for Acquired Resistance

Primary endpoint: progression-free survival

Activating EGFR mutationProgression on gefitinibNo prior chemotherapy

N = 250

RAND

Cisplatin/Pemetrexed

IMPRESS TRIAL

PI: Tony Mok & Jean-Charles Soria

Cisplatin/Pemetrexed+ ongoing gefitinib

Chemotherapy +/- Ongoing EGFR TKI for Acquired Resistance, with Retreatment

Primary endpoint: progression-free survival

PI: Leora Horn (Vanderbilt)

Advanced NSCLCActivating EGFR mutationResp to EGFR TKI>4 moNo prior chemotherapy

PS 0/1N = 120

RAND

Cis or Carbo/Pemetrexed+ ongoing erlotinib

Stratification by:

EGFR mut’n exon 19 vs. exon 21

Time to progression on EGFR TKI <1 yr vs. >1 yr

PS 0 vs. 1

Cis or Carbo/Pemetrexed

Erlotinib re-treatment

Chemotherapy +/- Ongoing Crizotinib for Acquired Resistance in ALK-Positive NSCLC

Co-primary endpoints: Progression-free survival Response rate, pemetrexed alone

ALK rearrangementProgression on crizotinib

after response or SD>3 moNo prior pemetrexed

N = 114

RAND

Pemetrexed alone

PI: D. Ross Camidge

Pemetrexed + ongoing+ crizotinib

SWOG 1300 (in development)

Chemo Without TKI Can Be Followed by Re-treatment

Oxnard, Clin Cancer Res, 2011

EGFR TKI Re-treatment after Acquired Resistance: DFCI/MGH Experience

• Retrospective, 24 pts (over 9.5 yrs) with activating EGFR mutation after AR to 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 of EGFR TKI (PFS 4.4 vs. 1.9 mo for 6 mo interval off EGFR TKI)

Heon, ASCO 2012, A#7525

MISSION Trial of Sorafenib vs. Placebo: PFS based on EGFR mutation status

Biomarker*treatment interaction analysis: p-value=0.015

Patients with EGFR mut (in tumor or plasma)• 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

MISSION Trial of Sorafenib vs. Placebo: OS based on EGFR mutation status

Patients 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=0.023

Mok, ESMO 2012

Are Repeat Biopsies Mandatory, Desirable, or Neither?

Yu, Clin Cancer Res, 2013

Not standard of care, relatively low probability of being immediately actionable, but repeat biopsies are likely to drive our understanding and future treatments in this setting.

• SCLC in 3-15%

• Potential insight re: prognosis (+/- value of ongoing TKI?)

• Otherwise, uncommon to find actionable result with current approved agents

N=155

Conclusions on Clinical Management of 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 by

re-treatment

Conclusions on Clinical Management of 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 special

population – consider clinical trials

• Role for repeat biopsy?– Uncommon to have actionable result today– Very likely to increase our understanding of the field and

identify future treatment options