Targeted Therapy What the Surgeon Needs to Know

Transcription

1 Targeted Therapy What the Surgeon Needs to Know AATS Focus in Thoracic Surgery 2014 David R. Jones, M.D. Professor & Chief, Thoracic Surgery Memorial Sloan Kettering Cancer Center

2 I have no disclosures

3 The Personalized Cancer Care Continuum Meric-Bernstam F et al. JCO 2013

4 Categories of Genomic Alterations and Technologies for Detection MacConaill LE, J Clin Oncol 2013

5 Evolution of Multiplexed Testing Platforms Now-Gen MSK LC-MAP 8 genes Point mutations only Next-Gen MSK IMPACT 409 genes Point mutations, deletions, insertions, amplifications Comparable time and cost

6 Actionable Targets in Lung Adenocarcinomas Unknown 75% Unknown 60% EGFR Kris M et al. IASLC 2012 Targeted Therapies Conference

7 LCMC: Frequency of Oncogenic Drivers 733 Specimens with All 10 Drivers Assayed Kris JAMA 2014

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9 Survival with the five most frequent oncogenic drivers group=alk group=doub group=egfr(o) group=egfr(s) group=kras YEARS Altered Gene N Median Survival (95% CI) EGFR (sensitizing) years (2.7 to 5.4) EGFR (other) years (2.2 to 6.2) ALK years (3.0 to NA) KRAS years (1.9 to 3.6) Two Drivers years (1.6 to 4.6) p=0.001

10 Scientific Breakthrough of the Year

11 PD1 Pathway Checkpoint Inhibitors Bristol Myers Squib

12 Immunomodulators in NSCLC Nivolumab: a fully human IgG4 monoclonal antibody that acts as an immunomodulator by blocking ligand activation of the programmed cell death 1 (PD-1) receptor on activated T cells. Ipilimumab: (FDA) approved for the treatment of melanoma, is a monoclonal antibody that activates the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

13 What is the role of surgery in the era of targeted therapy for NSCLC?

14 Role of Surgery in the Molecularly-Targeted Era Surgical specimens are more valuable than biopsy or cytology specimens in understanding tumor heterogeneity Surgery is a therapeutic modality in the era of targeted therapy Surgery plays a role in personalized therapy and discovery in the peri-operative period Personalization of surgical procedures based on lung cancer subtypes.

15 Surgical Specimens and Tumor Heterogeneity Cell number not the issue ( cells adequate for PCR) Specimen quality is the issue (snap-frozen to prevent degradation of RNA) Driver mutation heterogeneity in NSCLC poorly understood Results varied for EGFR (10-86%) Recent Japanese study suggests little variation Targeted therapy pressure on the tumor results in changes in driver mutations (new mutations, new drivers) Surgical specimens: better quality RNA, improved understanding of tumor heterogeneity post-therapy Yatabe et al. J Clin Oncol 2011 Mitsudomi T et al., Nat Rev Clin Oncol 2013

16 Classes of Tumor Heterogeneity in Lung Adenocarcinoma Mitsudomi T et al., Nat Rev Clin Oncol 2013

17 ALCHEMIST-Related Adjuvant Therapy Trials (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials) A Stage IB- IIIA NSCLC Complete Surgical Resection Screen for EGFR mutation+ cancers Adjuvant Therapy (if indicated) R a n d o m i z e Erlotinib X 2 years Placebo E4517 Stage IB- IIIA NSCLC Complete Surgical Resection Screen for ALK+ cancers Adjuvant Therapy (if indicated) R a n d o m i z e Crizotinib X 2 years Placebo

18 LCMC 3.0: Core Neoadjuvant Care and Research Paradigm - Clinical Stage I-IIIA Lung Cancers - Operable -Resectable Current 5 Year Survival < 50% Primary Endpoint: Major Pathologic Response Clinical Goal: Double MPR Rate Neoadjuvant Therapy SURGERY Assess pathologic response Postoperative Therapy Recurrence Biopsy #1 NextGen Genotyping RNA Seq Biopsy #2 NextGen Genotyping RNA Seq Biopsy #3 NextGen Genotyping RNA Seq

19 Induction Targeted Therapy Followed by Surgery Journal of Thoracic Oncology

20 Surgery as a Therapeutic Modality in Oligometastatic Disease A local therapy (surgery vs. RT) is indicated in selected cases of localized metastatic disease Lung, adrenal, bone, lymph nodes, liver, brain, pleural implant Increased numbers of these cases for consideration Depends on the morbidity, invasiveness, and impact on quality of life of the surgical procedure Ultimately will also depend on the cost of the approach related to the outcome (i.e. value)

21 Surgery is a Therapeutic Modality in the Era of Targeted Therapy Surgery is therapeutic in localized tumor(s) with acquired resistance when it occurs (it occurs in all patients) Cytotoxic chemotherapy largely ineffective after TKIs Cancer stem cells resistance to cytotoxic chemotherapy Tumor genomic information following resection highly relevant for subsequent therapy if/when recurrence Identification of mutations associated with acquired resistance New driver mutations, new tumor histologies (large cell, small cell) Mitsudomi T et al., Nat Rev Clin Oncol 2013 xx

22 Role of Surgery in Managing Resistance in the Treatment of Lung Cancer Mitsudomi T et al., Nat Rev Clin Oncol 2013

23 Tumor Boards of the Future: What s Missing? Roychawdhury S et al., Sci Translat Med 2011

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25 Surgery Personalization by Tumor Subtype Should all tumors receive the same procedure? Tumor size Specific histologic morphologies Nodal dissection/sampling GGO vs. semi-solid lesions Are there exceptions to the R0 oncologic principle of resection? Multiple GGO or subcentimeter lesions Could surgery be used as adjuvant therapy for earlystage lung cancer?

26 Surgery in the Era of Targeted Therapy Conclusions New day in oncologic surgery New challenges and new opportunities The era of molecular oncology is here to stay Role of surgery/surgeons depends on quality, outcomes, value New opportunities to collaborate with others in the diagnosis, treatment, follow-up of cancer patients

27 Approved Oncology Drugs with Anti-Tumor Activity in Specific Molecular Subsets Sleijfer et al. J Clin Oncol 2013

28 Exploratory integrative sequencing of tumors for personalized oncology Roychawdhury S et al., Sci Translat Med 2011

29 Genomic Alterations in Common Solid Tumor Malignancies Garraway LA, J Clin Oncol 2013

30 Impact of MSK Impact MSK Patients with Thoracic Cancers Scorecard - October 2014 Gene Targets in NCCN Guidelines 7 Targeted Drugs in NCCN Compendia 12 Gene Targets for Investigational Agents 17 Trials of Targeted Therapies for Specific Genes 30