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Home , Sotorasib, Trastuzumab deruxtecan

Precision Medicine in 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

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 , PLUS 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, ) 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 + [ or ] or fam- 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 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 + 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 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 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 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 (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. All doses: 20.6% 3‐mo PFS KM estimate: Probability • All doses: 58.5% 0.25 • 960 mg: 59.7%

0.00 0 246 8 10 Number at risk Months All doses 42 32 18 2 1 1 Presented960 mgBy John25 Strickler at 20 2020 ESMO 12 World GI 0 0 0 Patient Incidence of Adverse Events

Treatment-related adverse Treatment-related adverse events events of any grade N = 59, n (%) N = 59, n (%) occurring in > 1 patients Any grade 27 (45.8) Diarrhea 10 (16.9) Grade ≥ 2 12 (20.3) Fatigue 6 (10.2) Grade ≥ 3 3 (5.1) Grade ≥ 4 0 (0.0) Nausea 2 (3.4) Blood alkaline phosphatase Dose-limiting toxicities 0 (0.0) 2 (3.4) increase Serious AEs 0 (0.0) Blood creatine 2 (3.4) phosphokinase increase Fatal AEs 0 (0.0) Anemia 3 (5.1) AEs leading to treatment 0 (0.0) Vomiting 2 (3.4) discontinuation • Grade 3 treatment-related adverse events: Diarrhea (2/59, 3.4%) and Anemia (1/59, 1.7%)

Presented By John Strickler at 2020 ESMO World GI Adagrasib in mCRC

Hypothesis: Despite activity of KRASG12C inhibition, reactivation of RAS/MAPK pathway signaling may occur through adaptive feedback mediated by EGFR Combining adagrasib with cetuximab, an EGFR inhibitor, may enhance inhibition of KRASdependent signaling or overcome adaptive feedback and improve clinical outcomes

Taberno, ESMOGI 2021 Summary

• HER2 targeted therapies for HER2+ mCRC, while not FDA approved yet, are NCCN guideline listed • mBRAF/EGFR targeting improves PFS and OS compared with chemotherapy plus cetuximab and is FDA approved and NCCN guideline listed. • RAS targeting is finally a reality (at least for KRAS G12C) and other RAS inhibitors are in development as are combinations