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Mace L. Rothenberg, M.D.

Biomarkers in Colorectal Cancer Management: KRAS Mutations and EGFR Inhibitors. Mace L. Rothenberg, M.D. Professor of Medicine Ingram Professor of Cancer Research. Conflict of Interest Disclosure. Consultant or Advisory Role. Stock Ownership. Biomarkers in CRC Management.

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Mace L. Rothenberg, M.D.

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  1. Biomarkers in Colorectal Cancer Management: KRAS Mutations and EGFR Inhibitors Mace L. Rothenberg, M.D. Professor of Medicine Ingram Professor of Cancer Research

  2. Conflict of Interest Disclosure Consultant or Advisory Role Stock Ownership

  3. Biomarkers in CRC Management What is a biomarker? A specific, measurable, physical trait that can be used as a surrogate for a process of interest The trait can be a physical finding, a drug level, activation status of a molecule, or imaging characteristic The process that it reflects should be clinically meaningful: tumor presence or absence, response to therapy, development of toxicity, etc.

  4. Biomarkers in CRC Management Definitions Prognostic Factor A measurement or characteristic present at the time of diagnosis that correlates with clinical outcome regardless of treatment Predictive Factor A measurement or characteristic present at the time of diagnosis or initiation of treatment that is associated with likelihood of response to therapy

  5. Biomarkers in CRC Management Relationship of efficacy with KRAS status in patients with irinotecan-refractory mCRC treated with irinotecan and escalating doses of cetuximab – the EVEREST experience S Tejpar, M Peeters, Y Humblet, JB Vermorken, G De Hertogh, W. De Roock, J. Nippgen, A. von Heydebreck, C. Stroh, E. Van Cutsem

  6. KRAS status and Outcome in CRC Patients Treated with Irinotecan and Standard or Escalating-Doses of Cetuximab: EVEREST Key Findings • Escalating cetuximab dose until Grade 2+ skin toxicity occurs results in higher RR (30% vs 16%) – but not PFS (median 4.8 vs 3.9 months) or OS (median 8.6 vs 10.0 months) than with standard doses • S Tejpar et al: ASCO 2007, Abst. 4037 • Association of skin rash with PFS was present in KRAS wt and mutant subsets (but stronger in KRAS wt) • There was a non-significant trend towards higher RR in the cetuximab dose escalation arm only in KRAS wt patients (42% vs 30%). • No responses were seen in KRAS mutant patients, regardless of cetuximab dose. In fact, the rate of SD patients in the dose escalation arm was lower than the standard arm (33% vs 45%)

  7. KRAS status and Outcome in CRC Patients Treated with Irinotecan and Standard or Escalating-Doses of Cetuximab: EVEREST Conclusions • Patients with KRAS wt tumors benefited from irinotecan + cetuximab treatment Agree • In the dose escalation arm, a trend towards increased responses was observed in patients with KRAS wild-type tumors Yes, but the 39% relative improvement in RR was not matched by the 14% improvement in PFS • Dose escalation did not improve the efficacy in KRAS mutant tumors Agree

  8. KRAS status and Outcome in CRC Patients Treated with Irinotecan and Standard or Escalating-Doses of Cetuximab: EVEREST Conclusions • Skin toxicity and KRAS status are independent predictors of outcome Yes, but KRAS was the much stronger of the two • Predictive markers that act independently of KRAS were identified But these will only help us if we understand their biological significance

  9. Biomarkers in CRC Management K-Ras status and efficacy of 1st-line treatment of patients with mCRC with FOLFOX ± cetuximab: OPUS experience C. Bokemeyer, I. Bondarenko, J. T. Hartmann, F. G. De Braud, C. Volovat, J. Nippgen, C. Stroh, I. Celik, P. Koralewski Abstract #4000

  10. KRAS status and 1st-line FOLFOX ± cetuximab: OPUS Key Findings • In unselected patients, the addition of cetuximab to FOLFOX improves RR but not PFS

  11. FOLFOX ± Cetuximab RR in KRAS wild-type 70 24% absolute  65% relative  61 60 50 37 40 Response rate (%) 30 20 10 0 FOLFOX Cetuximab + FOLFOX KRAS wt

  12. FOLFOX ± Cetuximab PFS in KRAS wild-type 1.0 Progression HR = 0.57 for FOLFOX + cetuximab 0.9 0.8 0.7 0.6 Kaplan-MeierEstimate 0.5 0.4 0.3 0.2 0.1 0.0 12 4 6 8 10 0 2 Progression-free time (months) Cetuximab + FOLFOX FOLFOX

  13. FOLFOX ± Cetuximab RR in KRAS mutant 60 16% absolute  33% relative  49 50 40 33 Response rate (%) 30 20 10 0 FOLFOX Cetuximab + FOLFOX KRAS mt

  14. FOLFOX ± Cetuximab PFS in KRAS mutant 1.0 Progression HR = 1.83 for FOLFOX + cetuximab 0.9 0.8 0.7 0.6 Kaplan-MeierEstimate 0.5 0.4 0.3 0.2 0.1 0.0 12 4 6 8 10 0 2 Progression-free time (months) Cetuximab + FOLFOX FOLFOX

  15. KRAS status and 1st-line FOLFOX ± cetuximab: OPUS 12% absolute  32% relative  60 70 61 49 60 50 50 40 33 37 40 Response rate (%) Response rate (%) 30 30 20 20 10 10 0 0 FOLFOX Cetuximab + FOLFOX FOLFOX Cetuximab + FOLFOX KRAS wt KRAS mt

  16. KRAS status and 1st-line FOLFOX ± cetuximab: OPUS 60 70 28% absolute  46% relative  61 49 60 50 50 40 33 37 40 Response rate (%) Response rate (%) 30 30 20 20 10 10 0 0 FOLFOX Cetuximab + FOLFOX FOLFOX Cetuximab + FOLFOX KRAS wt KRAS mt

  17. KRAS status and 1st-line FOLFOX ± cetuximab: OPUS Toxicity and Tolerability • Patients treated with FOLFOX + cetuximab received roughly the same chemotherapy doses and dose intensity as those treated with FOLFOX alone But … • There was a difference in patterns of toxicity based on KRAS status: • Patients with KRAS wt tumors treated with FOLFOX + cetuximab tended to have a higher rate of Grade 3/4 hematological and GI toxicities than those treated with FOLFOX alone • Patients with KRAS mutant tumors treated with FOLFOX + cetuximab had lower rates of these toxicities

  18. KRAS status and 1st-line FOLFOX ± cetuximab: OPUS Conclusions • Addition of cetuximab to 1st-line FOLFOX  RR and PFS in patients with KRAS wt tumors Agree • Patients with KRAS mutant tumors do not profit from the addition of cetuximab Agree but … • Is it possible that patients with KRAS mutant tumors are harmed by the addition of cetuximab to FOLFOX? • Trend towards lower RR and shorter PFS when compared to those treated with FOLFOX alone is of concern.

  19. KRAS status and 1st-line FOLFOX ± cetuximab: OPUS Questions and Concerns - 1 • Is this effect limited to FOLFOX or is it seen with other regimens like FOLFIRI • See Van Cutsem - CRYSTAL presentation (Abst #2) – Sunday, June 1 and Cervantes poster (Abst #4129), Monday, June 2 • Is this effect limited to cetuximab or is it also observed with panitumumb? • See Cohn PRECEPT poster (Abst #4127) – Monday, June 2

  20. KRAS status and 1st-line FOLFOX ± cetuximab: OPUS Questions and Concerns - 2 • Is this effect limited to 1st-line therapies or is it seen in all lines of therapy? • See Di Fiore poster discussion (Abst #4035) – Sunday, June 1 • Is this effect seen with EGFR mAbs when used as a single agent? • Apparently not (Amado – J Clin Oncol – 2008) These findings will determine whether KRAS status should be established prior to the use of EGFR mAbs in patients with mCRC

  21. Possible Mechanisms for Resistance of KRAS Mutated Tumors to EGFR Inhibitors • Ras-induced up-regulation of VEGF • Zachary & Gliki: Cardiovasc Res 49:568-581, 2001 • Activation of Ras  terminal differentiation and  tumor stem cell population • KM Haigis et al: Nature Genetics 40:600-608, 2008 • K-Ras mutation   DNA methylation   expression of tumor suppressor and apoptotic genes • SK Patra: Exp Cell Res 314:1193-1201, 2008 • KRAS mutation   expression or activity of DNA repair genes • Pure speculation

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