Approved and Emerging Targeted Therapies for Molecularly Altered NSCLC

PRACTICE AID Approved and Emerging Targeted Therapies for Molecularly Altered NSCLC

NSCLC Is Complex and Heterogeneous

Molecular Subtyping of Adenocarcinoma1-3

 KRAS mutation  EGFR mutationa  ALK fusiona Other  ROS1 fusiona 18%  RET fusiona  NTRK1 fusiona  BRAF mutationa NSCLC  MET exon 14 mutationa 62%  HER2 mutation Adenocarcinoma  PIK3CA mutation 20%  Squamous cell HRAS mutation  carcinoma NRAS mutation  AKT mutation  MAP3K1 mutation  Unknown

FDA-Approved Targeted Therapies for NSCLC With Genomic Alterations

Molecular Approved Companion Drug Approved Indication(s) Recommended Dose Alteration Diagnostic(s)

1L (NCCN preferred) FoundationOne CDx; VENTANA Alectinib 600 mg PO BID with food metastatic ALK+ NSCLC ALK (D5F3) CDx Assay

Vysis ALK Break 90 mg PO QD for 7 d, then 180 mg Brigatinib 1L metastatic ALK+ NSCLC Apart FISH Probe Kit PO QD (with/without food)

ALK FoundationOne CDx; rearrangement Ceritinib 1L metastatic ALK+ NSCLC VENTANA ALK 450 mg PO QD (with food) (D5F3) CDx Assay

FoundationOne CDx; Crizotinib 1L metastatic ALK+ NSCLC VENTANA ALK 250 mg PO QD (D5F3) CDx Assay; Vysis ALK Break Apart FISH Probe Kit

2L metastatic ALK+ NSCLC after PD on alectinib or ceritinib as first ALK inhibitor; Lorlatinib N/A 100 mg PO QD 3L metastatic ALK+ NSCLC after PD on crizotinib and ≥1 other ALK inhibitor

Access the activity, “It’s Precisely the Time for More Precision in Genomic Testing and Targeted Treatment of NSCLC,” at PeerView.com/NEN40 PRACTICE AID Approved and Emerging Targeted Therapies for Molecularly Altered NSCLC

FDA-Approved Targeted Therapies for NSCLC With Genomic Alterations (Cont’d)

Molecular Approved Companion Drug Approved Indication(s) Recommended Dose Alteration Diagnostic(s)

BRAF V600E Dabrafenib 1L metastatic BRAF V600E FoundationOne CDx; Dabrafenib: 150 mg PO BID mutation + trametinib mutation–positive NSCLC Oncomine Dx Target Test (without food); trametinib: 2 mg QD

1L (NCCN preferred) unresectable or metastatic EGFR exon 19 deletion or exon 21 L585R mutation–positive FoundationOne CDx; Osimertinib 80 mg PO QD (with/without food) NSCLC; 2L metastatic EGFR cobas EGFR Mutation Test v2 T790M mutation–positive NSCLC with PD on or after an EGFR TKI

1L metastatic EGFR exon 19 Therascreen EGFR RGQ Gefitinib deletion or exon 21 L858R PCR Kit; cobas EGFR Mutation 250 mg PO QD (with/without food) mutation–positive NSCLC Test v2; FoundationOne CDx

Any line metastatic EGFR exon cobas EGFR Mutation Test v2; Erlotinib 19 deletion or exon 21 L858R 150 mg PO QD (on empty stomach) FoundationOne CDx mutation–positive NSCLC

EGFR mutation

1L metastatic NSCLC, EGFR exon 19 deletion, exon 21 L858R mutations, or other nonresistant EGFR mutations Therascreen EGFR RGQ Afatinib 40 mg PO QD (S768I, L861Q, and/or G719X); PCR Kit; FoundationOne CDx 2L metastatic squamous NSCLC after PD on platinum-based chemo

1L metastatic EGFR exon 19 Therascreen EGFR RGQ Dacomitinib deletion or exon 21 L858R 45 mg PO QD (with/without food) PCR Kit mutation–positive NSCLC

1L metastatic EGFR exon 19 Erlotinib cobas EGFR Mutation Test v2; Erlotinib: 150 mg PO QD; deletion or exon 21 L858R + ramucirumab FoundationOne CDx ramucirumab: 10 mg/kg IV Q2W mutation–positive NSCLC

FDA-Approved Targeted Therapies for NSCLC With Genomic Alterations (Cont’d)

Molecular Approved Companion Drug Approved Indication(s) Recommended Dose Alteration Diagnostic(s)

MET exon 14 1L metastatic MET exon 14 skipping Capmatinib skipping mutation–positive FoundationOne CDx 400 mg PO BID (with/without food) mutation NSCLC

All lines metastatic NTRK fusion–positive tumors that Entrectinib have no satisfactory alternative N/A 600 mg PO QD treatments or the show PD following treatment NTRK1/2/3 fusion All lines metastatic NTRK fusion–positive tumors that Larotrectinib have no satisfactory alternative N/A 600 mg PO QD treatments or the show PD following treatment

1L metastatic RET <50 kg: 120 mg PO BID; RET Selpercatinib N/A fusion fusion–positive NSCLC ≥50 kg: 160 mg PO BID

1L metastatic Crizotinib Oncomine Dx Target Test 250 mg PO BID ROS1-positive NSCLC

ROS1 rearrangement

1L metastatic Entrectinib N/A 600 mg PO QD ROS1-positive NSCLC

Investigational Targeted Therapies for NSCLC With Genomic Alterations

Target Treatment Stage Drug Study ID/Trial Identifier FDA or NCCN Recognition Category (Phase)

Alectinib NCT03456076 Adjuvant (3) N/A

ALK Ensartinib eXalt3/NCT02767804 1L (3) N/A rearrangement

Lorlatinib NCT03052608 1L (3) N/A

BRAF V600E Encorafenib PHAROS/NCT03915951 1L or 2L (2) N/A mutation + binimetinib

Erlotinib NEJ1026/UMIN000017069 1L (3) NCCN recommendation + bevacizumab

Gefitinib NEJ009/UMIN000006340 1L (3) N/A + chemo

EGFR mutation Osimertinib ADAURA/NCT02511106 Adjuvant (3) N/A

Osimertinib FLAURA2/NCT04035486 1L (3) N/A + chemo

Osimertinib TORG1833/CTI-184146 1L (2) N/A + ramucirumab

JNJ-6372 CHRYSALIS/NCT02609776 2L (2) FDA breakthrough

Osimertinib EA5162/NCT03191149 2L (2) N/A EGFR exon 20 mutation Poziotinib NCT03066206 2L (2) N/A

Mobocertinib TAK-788-3001/NCT04129502 1L (3) N/A

Investigational Targeted Therapies for NSCLC With Genomic Alterations (Cont’d)

Target Treatment Stage Drug Study ID/Trial Identifier FDA or NCCN Recognition Category (Phase)

[Fam-] trastuzumab DESTINY-Lung01/ 2L+ (2) FDA breakthrough deruxtecan NCT03505710

Ado-trastuzumab HER2 mutation NCT02289833 2L+ (2) NCCN recommendation emtansine

Poziotinib NCT03066206 1L+ (2) N/A

AMG 510 CodeBreak 200/NCT04303780 2L+ (3) FDA fast track

KRAS G12C LY3499446 NCT04165031 2L+ (2) N/A mutation

MRTX849 KRYSTAL-1/NCT03785249 1L+ (2) N/A

Cabozantinib NCT01639508 1L+ (2) N/A

Capmatinib GEOMETRY/NCT02414139 1L or 2L (2) N/A MET amplification Crizotinib PROFILE 1001/NCT00585195 Any line (1) NCCN recommendation

Tepotinib VISION/NCT02864992 1L+ (2) N/A

Crizotinib PROFILE 1001/NCT00585195 Any line (1) NCCN recommendation

MET exon 14 skipping Savolitinib NCT02897479 2L+ (2) N/A mutation

Tepotinib VISION/NCT02864992 1L+ (2) FDA breakthrough

Investigational Targeted Therapies for NSCLC With Genomic Alterations (Cont’d)

Target Treatment Stage Drug Study ID/Trial Identifier FDA or NCCN Recognition Category (Phase)

Repotrectinib NCT03093116 1L or 2L (2) N/A

NTRK fusion

Selitrectinib NCT03215511 1L+ (2) N/A

Cabozantinib NCT01639508 1L+ (2) NCCN recommendation

RET Pralsetinib ARROW/NCT03037385 1L or 2L (2) FDA breakthrough rearrangement

Vandetanib NCT01823068 2L+ (2) NCCN recommendation

Ceritinib NCT01964157 1L+ (2) NCCN recommendation

ROS1 Lorlatinib NCT01970865 2L+ (2) NCCN recommendation rearrangement

Repotrectinib TRIDENT-1/NCT03093116 1L+ (2) FDA fast track

a Genomic alterations in lung adenocarcinoma with FDA-approved targeted therapies. 1L: first line; 2L: second line; AE: adverse event; ALK: anaplastic lymphoma kinase; BID: twice daily; EGFR: epidermal growth factor receptor; HER2: human epidermal growth factor receptor 2; MAP3K1: mitogen-activated protein kinase kinase kinase 1; NCCN: National Comprehensive Cancer Network; NSCLC: non–small cell lung cancer; NTRK: neurotrophic tyrosine receptor kinase; PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PO: oral administration; Q2W: every 2 weeks; QD: once daily. 1. NCCN Clinical Practice Guidelines in Oncology. Non–Small Cell Lung Cancer. Version 5.2020. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. 2. Lindeman NI et al. J Thorac Oncol. 2018;13:323-358. 3. Kalemkerian GP et al. J Clin Oncol. 2018;36:911-919. Access the activity, “It’s Precisely the Time for More Precision in Genomic Testing and Targeted Treatment of NSCLC,” at PeerView.com/NEN40 PRACTICE AID Advanced NSCLC Molecular Testing Guidelines: Latest Updates and Best Practices

Why Test Lung Cancer Patients for Genomic Alterations?

• Genomic alterations are common in nonsquamous NSCLC (approximately 50%) • Targeted therapies produce better treatment outcomes (eg, higher response rates, improved quality of life) compared with chemotherapy as treatment of NSCLC with genomic alterations • Immunotherapy has low efficacy and a high risk of serious adverse events in patients with NSCLC with molecular driver alterations

Which Molecular Targets Are Relevant for Testing in NSCLC?

Molecular alterations to test for in patients with newly diagnosed stage IV NSCLC

Genotypes with approved Genotypes with emerging targeted therapies targeted therapies q EGFR mutations q EGFR exon 20 mutations q ALK rearrangements q HER2 mutations q ROS1 rearrangements q KRAS G12C mutations q BRAF V600E mutations q MET amplifications q NTRK fusions q Many other promising targets q MET exon 14 skipping mutations with matched therapies are q RET fusions undergoing investigation in trials

Access the activity, “It’s Precisely the Time for More Precision in Genomic Testing and Targeted Treatment of NSCLC,” at PeerView.com/NEN40 PRACTICE AID Advanced NSCLC Molecular Testing Guidelines: Latest Updates and Best Practices

Who Needs Molecular Testing and When Should it Occur?

q Step 1: Distinguish between small cell lung cancer vs non–small cell lung cancer q Step 2: If NSCLC à determine subtype (squamous, adenocarcinoma, large cell, etc) q Step 3: Upfront molecular testing à all patients with newly diagnosed stage IV NSCLCa should undergo molecular testing as quickly as possible to guide therapeutic decisions ü Adenocarcinoma ü Adenosquamous ü NOS ü Other nonsquamous histologies ü Squamous, if atypical presentation (light/never smoker) or incompletely sampled q Step 4: Molecular testing should be repeated when patients develop resistance or disease progression while on targeted therapy

Which Molecular Testing Techniques Should be Used for Detection of Dierent Molecular Alterations in NSCLC?1

q Next-generation sequencing (NGS) is increasingly used for molecular testing in NSCLC ü Massively parallel approach that relies heavily on automation, data storage, and computational processing ü Overcomes many of the shortcomings of direct sequencing and allele-specific testing ü Allows quantitative analysis of infrequent alleles and simultaneous evaluation of multiple genes or even whole genomes ü Retains sensitivity even in specimens with low tumor cellularity ü Can identify new abnormalities that would not be detected by allele-specific testing ü Can often detect abnormalities that would historically be tested by FISH ü Upfront use of NGS has been found to be associated with substantial cost savings and shorter time-to-test results vs single gene testing strategies q Selection of testing method: Ensure the test can detect gene fusions and other alterations in addition to mutations ü DNA–NGS for mutations + rearrangements + amplifications • May not catch all rearrangements/fusions and has a low resolution for amplifications ü RNA–NGS for rearrangements is associated with improved detection of fusion events • RNA preserved with FFPE has a high fail rate

Which Molecular Testing Techniques Should be Used for Detection of Dierent Molecular Alterations in NSCLC?1

EGFR MET HER2 BRAF KRAS ALK ROS1 MET RET PD-L1 Protein NTRK (Sensitizing Exon 14 Mutation Mutation Mutation Rearrangement Rearrangement Amplification Rearrangement Expression Fusion and T790M) Mutation Tissue PCR + + – + + – – – – – – sequencing Tissue allele–specific PCR sequencing ++ ++ ++ ++ ++ – – – – – – Tissue FISH – – – – – ++ ++ ++ ++ – ++ Tissue IHC – – – – – ++ – – – ++ + Tissue NGS ++ ++ ++ ++ ++ + + + + – + ctDNA PCR + + + + + + – – + – – ctDNA NGS + + + + + + + + + – + Tissue RNA + + ++ + + ++ ++ + ++ – ++ ++: Highest sensitivity +: Lower sensitivity (higher chance of false negative) –: Not useful

When Should Liquid Biopsies Be Considered for Use?

• NCCN guidelines recommend plasma-based testing for all patients with advanced-stage, treatment-naïve lung cancer for whom tissue sampling may be infeasible or insufficient • Recent studies found that simultaneously adding plasma ctDNA analysis to tissue testing 75% enhanced the chances of detecting a relevant actionable mutation more actionable • Based on these findings, it is reasonable to consider plasma-based testing for every mutations found patient with advanced-stage, treatment-naïve lung cancer who has a tissue biopsy with tissue + • A new tissue biopsy and/or ctDNA plasma test also needs to occur when patients with plasma vs genotype-directed NSCLC develop resistance/disease progression while on targeted tissue alone TKI therapy

a There is emerging evidence from the ADAURA (osimertinib) trial that it may be beneficial to test for EGFR mutations in earlier disease settings (eg, stage I to stage III) and treat patients with EGFR TKI therapy following surgery. The recommended testing guidelines may change based on the results of this trial to include all patients (stage IB to stage IV) with newly diagnosed NSCLC. ALK: anaplastic lymphoma kinase; ctDNA: circulating tumor DNA; EGFR: epidermal growth factor receptor; FFPE: formalin fixed, paraffin embedded; FISH: fluorescence in situ hybridization; HER2: human epidermal growth factor receptor 2; IHC: immunohistochemistry; NGS: next-generation sequencing; NOS: not otherwise specified; NSCLC: non–small cell lung cancer; NTRK: neurotrophic receptor tyrosine kinase; PCR: polymerase chain reaction; PD-L1: programmed cell death ligand 1. 1. https://www.uptodate.com/contents/personalized-genotype-directed-therapy-for-advanced-non-small-cell-lung-cancer. Access the activity, “It’s Precisely the Time for More Precision in Genomic Testing and Targeted Treatment of NSCLC,” at PeerView.com/NEN40