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Advanced Colorectal Cancer ; Individualization of Treatment RET alterations

Advanced Colorectal Cancer ; Individualization of Treatment RET alterations. Bülent Orhan MD. Acibadem University Medical Oncology Department Bursa Turkey. RET Oncogene. Description RET Oncogene Ret alterations in different cancers Lung Cancer Thyroid Cancer Colon Cancer

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Advanced Colorectal Cancer ; Individualization of Treatment RET alterations

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  1. Advanced ColorectalCancer; Individualization of TreatmentRET alterations Bülent Orhan MD. AcibademUniversityMedicalOncologyDepartment Bursa Turkey

  2. RET Oncogene • Description RET Oncogene • Ret alterations in different cancers • Lung Cancer • Thyroid Cancer • Colon Cancer • New Drugs

  3. RET Oncogene • Rearranged During Transfection Proto-oncogene (RET) • Receptor tyrosine kinase • Defined as an oncogene by a classical transfection assay • Germline mutations associated with: • Multiple endocrine neoplasia, type IIA (MEN2A) • Multiple endocrine neoplasia, type IIB (MEN2B) • Medullary thyroid carcinoma

  4. RET: Receptor Tyrosine Kinase With Multiple Ligands RET GDNF NTRN ARTN PSPN GDNF family ligands Cadherin-like domain Cysteine-rich domain GFRα family GFRα3 GFRα4 GFRα2 GFRα1 Tyrosine kinase domain P P Isoform tails Adapted from: Mulligan LM. Nat Rev Cancer. 2014;14:173-186.

  5. RET Activating Alterations Differ in Different Conditions • All lead to constitutive activation MEN2BKinase domain mutations RETWild type FMTCIntracellulardomain mutations MEN2A and FMTCExtracellulardomain mutations * * P P P P P Lipid raft * * * P * * * P P Adapted from: Mulligan LM. Nat Rev Cancer. 2014;14:173-186.

  6. RET Activating Alterations Differ in Different Conditions • All lead to constitutive activation • In solid tumors, rearrangements are increasingly a focus for potential therapy MEN2BKinase domain mutations RET Rearrangements RETWild type FMTCIntracellulardomain mutations MEN2A and FMTCExtracellulardomain mutations * * P P RET-PTC P P P Lipid raft P * * * P * * * P P P Adapted from: Mulligan LM. Nat Rev Cancer. 2014;14:173-186.

  7. RET Downstream Activation RET Activation JNK AKT PDK RAF Kinase JUN PLCy PKC SH3 GRB2 RAS SOS STATs GAP PI3-kinase mTOR ERK Proliferation Nucleus Adapted from: Airaksinen MS, et al. Nature Reviews Neuroscience. 2002;3:383-394.

  8. RET Alterations Differ in Different Conditions G533 C609C611C618C620C630C634 A. MTCMEN2 mutations MEN2AFMTC G691 Modifying Variants E768 Y791 L790Y790V804 FMTC A883S891M918 FMTC MEN2B Adapted from: Mulligan LM. Nat Rev Cancer. 2014;14:173-186.

  9. RET Alterations Differ in Different Conditions G533 C609C611C618C620C630C634 A. MTCMEN2 mutations B. Papillary thyroid carcinoma MEN2AFMTC 713 CCDC6 101 RET-PTC1 NCOA4 238 713 RET-PTC3 G691 C. Lung adenocarcinoma Modifying Variants E768 KIF5B 575 713 Y791 L790Y790V804 FMTC KIF5B-RET D. Chronic myelomonocytic leukemia A883S891M918 FMTC MEN2B BCR 426 713 BCR-RET FGFR1OP 375 713 FGFR1OP-RET Adapted from: Mulligan LM. Nat Rev Cancer. 2014;14:173-186.

  10. Amplification (25%) RET Aberrations(1.8%) Mutation (38.6%)

  11. Amplification (25%) RET Aberrations(1.8%) Mutation (38.6%)

  12. RET: Genetic Aberrations in 4871 Diverse Cancers Duplication (1.1%) Rearrangement (3.4%) Loss (1.1%) Amplification (25%) RET Aberrations(1.8%) Mutation (38.6%) No RET Aberrations (98.2%) Fusion (30.7%) N = 4871 n = 88 Kato S, et al. Clin Cancer Res. 2017;23:1988-1997.

  13. SUMMARY: RETMutations in Cancer: Kato S et al. • Medullary thyroid carcinoma • 43% to 71% of sporadic cases • Papillary thyroid carcinoma • 10% to 20%, but higher after radiation exposure Kato S, et al. Clin Cancer Res. 2017;23:1988-1997. Huang K, et al. Cell. 2018;173:355-370.

  14. RETMutations in Cancer • Non-small-cell lung cancer (NSCLC) • 1% to 2% of non-squamous NSCLC • Seen in other tumor types – but rarely • Seen in colon cancer % 1 • Wide spectrum of other tumor types with variants in RET • Only a subset are known to be activating • If you see a RET “mutation” in a molecular report, don’t assume it’s activating P P Kato S, et al. Clin Cancer Res. 2017;23:1988-1997. Wang R, et al. J Clin Oncol. 2012;30:43524-359.

  15. Lung Cancer & RET

  16. Mutation Spectrum in NSCLC NSCLC by Histology Others20% Squamous Cell Carcinoma Adenocarcinoma ROS12% Adenocarcinoma50% Squamous cell carcinoma 30% HER2/MEK2% BRAF/PIK3CA2% RET1% MET4% DDR22% Unknown mutation20% ALK5% PIK3CAamplification34% Unknownmutation39% PI3KCAmutation15% KRAS30% FGFR119% PTEN10% EGFR15% Chan BA, et al. Transl Lung Cancer Res. 2015;4:36-54.

  17. Current Molecular Testing Recommendations for Newly Diagnosed NSCLC From IASLC/CAP/AMP Recommended Testing for All Patients With Adenocarcinoma* • EGFR mutations • ALK and ROS1 translocations • BRAF • PD-L1 expression using IHC† • Broad multiplex/NGS panels preferred over single-gene testing to ID wider range of actionable aberrations • Appropriate as Part of Larger Panel; Either Initially or if Negative for EGFR, ALK, and ROS1 • KRAS • BRAF (if not already assessed) • RET • HER2 • MET • Not recommended as routine stand-alone assay *Consider in patients with squamous histology if younger, never/light smoking history, or small biopsy specimen. †To be addressed in future guidelines; current recommendation is to preserve samples for assessing biomarkers that predict response to immunomodulatory therapies. Lindeman NI, et al. J Thorac Oncol. 2018;13:323-358.

  18. Growing Indication: RET Fusion & Resistance to Prior TKI Therapy • Potential to assess RET alterations in the setting of resistance to therapies • Case reports: acquired ALK and RET fusions reported after resistance to osimertinib in EGFR-mutant NSCLC Offin M, et al. JCO Precision Oncology 2018:2;1-12 .

  19. Thyroid Cancer & RET

  20. Mutation Spectrum in Thyroid Cancer Sporadic Medullary*[1] Thyroid Cancer by Pathology[2] Papillary[3-5] Medullary 2% Hürthle Cell 2% Follicular 5% Unknownmutation10% Other/unknown5% PTEN2%I Anaplastic 1% PI3KCA3% • PI3KCAcopy gain 12% Papillary 89% BRAFV600E45% RAS10% Somatic RETmutation50% RAS40% RET/PTCfusions20% BRAF copy gain3% *Familial MTC: 100% germline RET mutation References in slidenotes.

  21. Testing for RET in Thyroid Carcinoma • Medullary thyroid carcinoma • Reflex testing for MUTATION testing should be considered • (The oncologist is going to ask for it anyway!) • Differentiated thyroid carcinoma (PTC, etc) • Very high surgical cure rate • No need to test presurgical diagnostic sample OR • Resection • Upon recurrence: TEST (for FUSION)

  22. RET Inhibitors

  23. RET Inhibitors Circa 2012 (Including Off Label)

  24. RET Multikinase Inhibitors in RET-Rearranged NSCLC: Best Response to Therapy • From an international registry of patients with RET-rearranged NSCLCs Gautschi O, et al. J Clin Oncol. 2017;35:1403-1410.

  25. RET Inhibitors in Medullary Thyroid Cancer: PFS With Multikinase Inhibitors • RET point mutations (most commonly M918T): nearly all of familial cases; ~ 50% of sporadic cases Phase III Trial in Patients With Progression of MTC[1] ITT Population Phase III Trial in Patients With Advanced MTC[1] • ITT Population Cabozantinib11.247.3 Placebo4.07.2 Median PFS, mos1-yr PFS, %HR (95% CI) 0.28 (0.19-0.40) 1.0 Vandetanib 300 mgPlacebo 1.0 0.8 0.8 0.6 0.6 PFS (Probability) PFS (Probability) 0.4 0.4 0.2 0.2 P < .001 0 0 0 2 4 6 8 10 12 14 16 18 20 22 0 6 12 18 24 30 36 Mos Mos Subgroup analysis suggested RET M918T associated with better efficacy Responsiveness regardless of RET M918T status 1. Elisei R, et al. J Clin Oncol. 2013;31:3639-3646. 2. Wells SA, et al. J Clin Oncol. 2012;30:134-141.

  26. RET Inhibitors in Differentiated Thyroid Cancer Locally advanced iodine refractory disease – RET not assessed 100 n207210 Median PFS, Mos10.85.8 SorafenibPlacebo 75 HR: 0.59 (95% CI: 0.45-0.76)P < .0001 PFS Probability (%) 50 25 0 0 100 200 300 400 500 600 700 800 Days From Randomization Brose MS, et al. Lancet. 2014;384:319-328.

  27. RET Inhibitor Potency Comparison Velcheti V, et al. IASLC 2017. Abstract OA 12.07. 1. Kodama T, et al. Mol. Cancer Ther. 2014:13;2910-2918. Roskoski R, et al. Pharmacol Research. 2018;1281-17. 2. Rahal R, et al. AACR 2017. Abstract B151. 3. Matsui J, et al. Int J Cancer. 2008;122:664-671. 4. Roskoski R. BiochemBiophys Res Comm. 2007;356:323-328. 5. O'Hare T, et al. Cancer Cell. 2009;16:401-412. 6. Gadaleta-Caldarola, et al. Future Medicine. 2015;11. 7. Wilhelm SM, et al. Int J Cancer. 2011;129:245-255.

  28. RET Inhibitor Potency Comparison LOXO-292 BLU-667 Velcheti V, et al. IASLC 2017. Abstract OA 12.07. 1. Kodama T, et al. Mol. Cancer Ther. 2014:13;2910-2918. Roskoski R, et al. Pharmacol Research. 2018;1281-17. 2. Rahal R, et al. AACR 2017. Abstract B151. 3. Matsui J, et al. Int J Cancer. 2008;122:664-671. 4. Roskoski R. BiochemBiophys Res Comm. 2007;356:323-328. 5. O'Hare T, et al. Cancer Cell. 2009;16:401-412. 6. Gadaleta-Caldarola, et al. Future Medicine. 2015;11. 7. Wilhelm SM, et al. Int J Cancer. 2011;129:245-255.

  29. Colon Cancer & RET Oncogene

  30. Colon Cancer & RET Oncogene First Description

  31. Colon Cancer & RET Oncogene

  32. New molecules and Emerging RET Therapies in Clinical Trials

  33. RET Inhibitor Potency Comparison LOXO-292 BLU-667 Velcheti V, et al. IASLC 2017. Abstract OA 12.07. 1. Kodama T, et al. Mol. Cancer Ther. 2014:13;2910-2918. Roskoski R, et al. Pharmacol Research. 2018;1281-17. 2. Rahal R, et al. AACR 2017. Abstract B151. 3. Matsui J, et al. Int J Cancer. 2008;122:664-671. 4. Roskoski R. BiochemBiophys Res Comm. 2007;356:323-328. 5. O'Hare T, et al. Cancer Cell. 2009;16:401-412. 6. Gadaleta-Caldarola, et al. Future Medicine. 2015;11. 7. Wilhelm SM, et al. Int J Cancer. 2011;129:245-255.

  34. Emerging RET Therapies in Clinical Trials • LOXO-292: • Phase I/II study (LIBRETTO)[1] • Primary endpoint: determination of MTD, recommended dose for further study • Secondary endpoints: PK, safety/tolerability, ORR (RECIST v1.1), DoR • BLU-667 • Phase I/II study(ARROW)[2] • Primary endpoint: determination of MTD, recommended phase II dose, AEs, ORR • Secondary endpoints: DoR, DCR, PFS, and OS RET BLU-667 1. Drilon AE, et al. ASCO 2018. Abstract 102. 2. Subbiah V, et al. Cancer Discov. 2018;8:836-849.

  35. 1. Drilon AE, et al. ASCO 2018. Abstract 102. 2. Subbiah V, et al. Cancer Discov. 2018;8:836-849.

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