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Precision Medicine in Colorectal Cancer 2021

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Precision Medicine in Colorectal Cancer 2021 Precision Medicine in Colorectal Cancer 2021 Michael Morse, MD Professor of Medicine Duke University Disclosures Biomarker Subgroups in CRC This lecture will not address MSI‐H and TMB‐H RAS mutation ± 45% PIK3CA/PTEN mutation 8% PIK3CA/PTEN mutation 1% p6 235-237, 2% 2% 1%2% 26% 2%2% Kinase inhibitor 8% MET inhibitor Anti‐HER2 Tx Wild type Anti‐PD‐1/PD‐L1 Anti‐EGFR therapies BRAF V600E BRAF inhibitor + anti‐EGFR ± MEK inhibitor Dienstmann. ASCO Ed Book. 2018. Slide credit: clinicaloptions.com Next‐generation sequencing results of TRIBE2 study BRAF V600E KRAS G12C HER2 Ampl HER2 Mut MSI‐H POLE mut TMB high Right sided 20% had “actionable” alterations Antoniotti C, Eur J Cancer. 2021 Aug 5;155:73‐84. BRAF V600E Targeting This section is courtesy John Strickler, MD BRAF V600E mutant mCRC has poor prognosis with chemotherapy Presented By Michael Lee at ASCO 2020 BRAFV600E mutations in metastatic CRC • ~5‐8% of CRC • Right sided • High grade • More likely to be MSI‐H • Poor prognosis • Limited benefit from anti‐EGFR therapy Strickler et al., Cancer Treat Rev. 2017 Nov;60:109‐119. Rationale for inhibition of BRAF + EGFR +/‐ MEK Presented By Eric Von Cutsem at 2018 ESMO GI Meeting BEACON CRC Phase 3 Study Design Kopetz et al., J Clin Oncol 38: 2020 (suppl; abstr 4039) Van Cutsem. JCO. 2019;[Epub]. Taberno. ESMO 2019. LBA32. Kopetz. NEJM. 2019;[Epub]. NCT02928224 BEACON: Updated Overall Survival Kopetz et al., J Clin Oncol 38: 2020 (suppl; abstr 4039) BEACON: Updated Objective Response Rates Kopetz et al., J Clin Oncol 38: 2020 (suppl; abstr 4039) BEACON: Updated Progression Free Survival Kopetz et al., J Clin Oncol 38: 2020 (suppl; abstr 4039) Overall Summary of Safety Kopetz et al., J Clin Oncol 38: 2020 (suppl; abstr 4039) ANCHOR CRC: A SINGLE‐ARM, PHASE 2 STUDY OF ENCORAFENIB, BINIMETINIB PLUS CETUXIMAB IN PREVIOUSLY UNTREATED BRAFV600E–MUTANT METASTATIC COLORECTAL CANCER Grothey, ESMO2020, LBA5 Recent prior studies in BRAF mutant CRC Presented By Michael Lee at ASCO 2020 Encorafenib + anti‐EGFR is the new standard of care for BRAFV600E mutated metastatic CRC • Can we give encorafenib + anti‐ EGFR 1st line? • Are there patient sub‐populations who need the triplet (anti‐MEK)? • What to do after progression? HER2 (ERBB2) targeting in mCRC HER2 in mCRC ~3% of patients with mCRC Usually left sided Primary resistance to EGFR monoclonal antibodies (cetuximab, panitumumab) Not mutually exclusive with RAS mutations Probably not prognostic Different ways to measure HER2 expression (IHC, ISH, NGS on tissue; NGS on ctDNA) Different studies used different criteria Ann Oncol. 2018;29(5):1108–1119. (More stringent) NGS (cutoff 6): Applying HERACLES diagnostic criteria, IHC and NGS show 92% concordance at the positive HER2 cutpoint and 99% concordance if equivocal cases are also considered positive Am J Clin Pathol. 2019 Jun 5;152(1):97-108 HER2 amplification by tissue vs ctDNA vs IHC Tissue NGS vs IHC: Applying HERACLES diagnostic criteria, IHC and NGS show 92% concordance at the positive HER2 cutpoint and 99% concordance if equivocal cases are also considered positive Am J Clin Pathol. 2019 Jun 5;152(1):97-108 International Cohort of mCRC tested for HER2+ by tissue (IHC, ISH, NGS) or blood (NGS) Raghav, ASCO2021;abstract 3589 Determining HER2 positivity-NCCN HER2 targeting (NCCN guidelines) for HER2 amplified and RAS/BRAF WT Trastuzumab+ [pertuzumab or lapatinib] or fam- trastuzumab deruxtecan nxki Initial Therapy: Pt not appropriate for intensive therapy Subsequent therapy Notes activity for fam-trastuzumab deruxtecan nxki in some with prior HER2-targeted treatment HER2 targeted therapy in mCRC Therapy Study Criteria Outcome Trastuzumab + Laptinib 1HERACLES-A HER2+ mCRC with PD post std tx ORR: 28%, SD 41% PII, N = 32 KRAS exon 2 wt mPFS 4.7m, mOS 10m Trastuzumab + Pertuzumab 2MyPathway HER2+ mCRC refractory to std tx ORR 31% (KRAS wt) PII, N = 84 (allowed mKRAS; 68 were wt) 3mPFS 5.3m (KRAS wt) 3mOS 14m (KRAS wt) Trastuzumab + Pertuzumab 4TRIUMPH HER2+ mCRC, refract to std tx ORR 35% PII, N = 17 (tissue) RAS wt mPFS 4.0m Trastuzumab + Pertuzumab 5TAPUR HER2+ mCRC, no std tx options ORR 25%, DCR 50% PII, N=28 No data on RAS mPFS 4 m; mOS 25m Trastuzumab + Tucatinib 6MOUNTAINEERP HER2+ mCRC, prior F, Ox, Iri, VEGF ORR 55%, SD 9% II, N = 26 RAS wt mPFS 6.2m, mOS 17m T-DM1 + pertuzumab 7HERACLES-B HER2+ mCRC, refract to std tx ORR 10%, SD 68% PII, N=30 RAS/BRAF wt mPFS 4.1 Fam-Trastuzumab 8DESTINY-CRC01 HER2+ mCRC , ≥2 prior regimens. ORR 45%; DOR 7m deruxtecan (T-Dxd) PII, N=54 RAS wt mPFS 6.9m; mOS 15.5 m 1Tosi F, 2020 Dec;19(4):256-262.e2. 2Meric-Bernstam, ASCO 2021; 3004. 3Meric-Bernstam, Lancet Oncol. 2019;20:518-530. 4Nakamura Y, ESMO 2019. 5Gupta R, GI ASCO 2020. 6Strickler, ESMO2019; 527PD. 7Sartore-Bianchi, ESMO Open. 2020;5(5):e000911. 7Yoshino ASCO2021;3505 Balancing efficacy and toxicity Adapted from M. Lee, ASCO2020 Other considerations: Need adequate HER2 expression Destiny-CRC01 cohorts with IHC2+/ISH- and IHC1+ had minimal benefit from T-Dxd HER2 IHC 3+ or 2+/ISH+ HER2 IHC 3+ or 2+/ISH+ Adapted from Yoshino ASCO2021;3505 Even among the HER2+, better response if IHC3+ Adapted from Yoshino ASCO2021;3505 mKRAS generally does not respond In MyPathway study Not known if T-Dxd has activity in mRAS Meric-Bernstam, ASCO 2021; 3004. Activity for T-Dxd in prior HER2 treated pts Adapted from Yoshino ASCO2021;3505 Resistance to HER2 targeted therapy Pts progressing After T + lapatinib ERBB2, RAS, PIK3CA mutations are associated with resistance to HER2 blockade in mCRC Siravegna, Cancer Cell 2018;34:148–162.e7. HER2 mutations generally do not respond, but…. HER2 mutations in ~ 2% of mCRC patients – Concurrent HER2 amplification and mutation found in ~ 0.5%. HER2 mutations clustered in TK, JM, TM, and EC domains. Mutations in the tyrosine kinase domain (L755S, V842I, D769Y, and K753E) increase kinase activity and are resistance to both anti-HER2 antibodies and small-molecule HER2 kinase inhibitors Mutations in the ECD, such as S310F and S310Y, lead to the increased dimerization of HER2 and subsequent signaling – Remain sensitive to both trastuzumab and HER2 TKIs Case report of patient with RAS WT metastatic CRC and a concurrent HER2 amplification and HER2 S310F mutation who responded to trastuzumab/lapatinib and briedly to T-Dxd Wang, J Natl Compr Canc Netw. 2021 Jun 30;19(6):670-674. Current anti-HER2 trials for metastatic CRC Trial Ph Treatment Line Comments Cetuximab + National irinotecan vs SWOG-1613 II ≥ 2nd cooperative Trastuzumab + group study pertuzumab NSABP Neratinib Primary foundation: II +Trastuzumab or ≥ 3rd endpoint PFS NCT03457896 Neratinib + Cetuximab Pyrotinib + ≥ 3rd Conducted in NCT03843749 II trastuzumab China Courtesy of John Strickler, MD KRAS G12C targeting in mCRC KRAS mutations in mCRC Most mutations are in glycine12 (G12), glycine13 (G13), and glutamine61 (Q61). These mutations prevent GAPs from accessing GTP so that hydrolysis is blocked, resulting in a persistently activated GTP‐bound state Merz, Front. Oncol., 11 March 2021 KRAS G12C in mCRC and inhibitors Drugs targeting KRAS directly are challenging to develop because of its small size, smooth surface, and strong binding affinity for GTP (and high amount of GTP present in cells) Sotorasib forms an irreversible, covalent bond with the cysteine residue of KRAS G12C, holding the protein in its inactive GDP bound Adagrasib is also a covalent inhibitor of KRASG12C that irreversibly and selectively binds KRASG12C in its inactive, GDP‐bound state KRAS has a protein resynthesis half life of 24 hrs Sotorasib (AMG510) CodeBreak100: Study Design Phase 1, Multicenter, Open-Label Study – Dose Escalation Dose Expansion – 2–4 patients enrolled in each cohort – Intra–patient dose Cohort 4 escalation allowed Key Eligibility a 960 mg a – Additional patients – Locally advanced or may be added to any metastatic malignancy dose deemed safe Cohort 3 – Received prior 720 mg Patients with standard therapies KRASG12C mutant – KRAS G12C mutation advanced tumors Cohort 2 as assessed by – Repeated oral daily Expansion dose 360 mg molecular testing of dosing with 21-day cycles determined tumor biopsies Safety Follow-up & Follow-up Safety – Treatment until disease & Follow-up Safety Long Term Follow-up Term Long Long Term Follow-up Term Long Screening / Screening Enrollment – No active brain Cohort 1 progression, intolerance, / Screening Enrollment metastases 180 mg or consent withdrawal – Radiographic scan every 6 weeks Primary endpoints: dose limiting toxicities (DLTs), safety Key secondary endpoints: PK, objective response rate, duration of response, disease control rate, PFS, duration of stable disease a30 (+7) days after end of treatment for safety follow-up; every 12 weeks for long term follow-up. PK: pharmacokinetics; PFS: progression-free survival. Target dose for expansion: 960mg Q.D. Presented By John Strickler at 2020 ESMO World GI Efficacy in CRC Best percent change in tumor burden from baseline 100 Efficacy measures N=42 80 60 PD PD Objective response rate 7.1% (3/42) 40 PD Disease control rate 76.2% (32/42) PD SD SD PD SD SD 20 PD SD SD SD SD SD* SD SD SD* SD SD* PD 0 PD SD SD -20 SD SD SD SD SD SD SD* SD SD SD SD* SD -40 PR* PR* PR* -60 Sum of Longest Diameters Sum of Longest -80 -100 *Treatment ongoing Planned Dose: 180 mg 360 mg 720 mg 960 mg Best Percent Change from Baseline in Baseline from Change Best Percent All 3 responses were confirmed and ongoing as of cutoff Progression-Free Survival All dose levels (N = 42) 1.00 960 mg (N = 25) PFS, month Median (min, max) All doses 4.0 (0.7, 11.0) 0.75 960 mg 4.2 (1.2, 5.7+) 6‐mo PFS KM estimate: 0.50 • +: censored value.
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