Targeted/Precision Therapies Beyond EGFR and ALK Alterations

Home , Larotrectinib

Targeted/precision therapies beyond EGFR and ALK alterations: novel therapies and mechanisms of resistance (ROS1, BRAF-V600E, NTRK, MET, RET, ERBB2, KRAS-G12C and others)

Daniel B. Costa, MD, PhD, MMSc Associate Professor of Medicine Harvard Medical School Medical Director Cancer Clinical Trials Office Thoracic Oncology Group Leader Division of Medical Oncology Beth Israel Deaconess Medical Center Disclosures

Relevant financial relationships with a commercial interest: _ Clovis Oncology, research funding (previous 2016) _ Boehringer Ingelheim Pharm. Inc., consulting/honoraria (previous 2016) _ Pfizer Inc., consulting/honoraria (previous 2017) _ Takeda/Millennium Pharmaceuticals, consulting/honoraria (previous 2016-2019) _ AstraZeneca, consulting/honoraria/research funding (previous 2016-2019)

Non-financial support (institutional research support): _ Merck Sharp & Dohme Corporation _ Pfizer _ Takeda/Millennium Pharmaceuticals _ Astrazeneca _ Merrimack Pharmaceuticals _ Novartis

“Off-label” use disclosure relevant to my presentation: _ To be indicated during presentation Outline • Historical view of non-small-cell lung cancer (NSCLC) from 2004 to 2019 • Background in evolution of kinase inhibitors for EGFR mutations and ALK rearrangements • Precision oncology for lung cancer in 2019 • Focus on ROS1 rearrangements (crizotinib, entrectinib) • Focus on BRAF-V600E mutation (dabrafenib/trametinib) • Focus on NTRK rearrangements (larotrectinib, entrectinib) • Focus on RET rearrangements • Focus on MET exon 14 skipping • Focus on ERBB2 exon 20 mutations • Focus on KRAS-G12C mutation

Presented by: Daniel B. Costa, MD, PhD, MMSc Clinical relevance and scope of the problem: Lung Cancer Evidence-based therapies for advanced non-small-cell lung cancer circa 2004 Medical Oncology management of evidence-based therapies for advanced non-small-cell lung cancer from BIDMC – Dec. 2019 Contemporary View of Lung Cancer 2007-2019: NSCLCs are heterogeneous at the genomic level

Adapted from: American Cancer Society (2014) Adapted from: Imielinski M. et al. Cell 150, 1107-1120 (2012)

EGFR mutations (~15%) squamous cell carcinoma unselected histology-based KRAS genomics-driven non-small-cell lung cancer (NSCLC) other/unknown mutations (~25%) cytotoxic adenocarcinoma cytotoxic precision therapies chemotherapies chemotherapies ALK rearrangements (1990s) (2000s) ROS1 (~5%) (2010s) rearrangements Adapted from: Shaw AT et al. N Engl J Med;368:2385-94 (2013) (~2%) Driver oncogene genotypes with kinase inhibitor approval/development (advanced lung adenocarcinoma) in 2019

Genetic aberrations that EGFR mutations can modulate gefitinib/erlotinib targeted or immune afatinib/dacomitinib therapies: osimertinib

differentiation vascular collapse

survival Driver proliferation oncogene

apoptosis senescence

kinase inhibitor : target Anaplastic lymphoma kinase (ALK) is an oncogene in NSCLC: Identification of ALK rearrangements/translocations in 2007 ALK rearrangements activate signaling pathways

Or Inversion Translocation

ALK ALK fusion protein*

PI3K RAS PLC-Y STAT3/5

AKT MEK PIP mTOR 2

BAD ErK S6K IP3

Cell survival Tumor cell proliferation

Soda M., et al. Nature. 2007 Aug 2;448(7153):561-6. Adapted from: Bang Y et al. Proc ASCO 2010;Abstract 3. ALK inhibitors (multitargeted TKIs) in clinical development in late 2007 - early 2010: crizotinib

A549 H3122 (KRAS G12S) (EML4–ALK E13;A20) crizotinib 0 0.1 1.0 0 0.1 1.0 (µM)

pALK

ALK 120kDa

pAKT

AKT 60kDa

actin 45kDa

RR (CR+PR) = 57% (95% CI: 46–68%) DCR (CR+PR+SD) = 87% (71/82)

crizotinib 250 mg BID Yasuda et al. J Thorac Oncol. 2012 Jul;7(7):1086-90. Kwak, E. et al. N Engl J Med 2010 Oct28; 363(18):1693-703. ALK TKI crizotinib as first line therapy for ALK rearranged NSCLC: PROFILE1014 – results

Solomon BJ et al N Engl J Med 2014;371:2167 Acquired resistance to crizotinib (pharmacokinetic or biologic) - crizotinib pharmacokinetic issues (major component): low serum conc., poor CNS penetration, p-glycoprotein - crizotinib biological resistance: ALK kinase domain mutations or bypass oncogenes

ALK mutations:

L1196M Activated 1151Tins oncogenes: C1156Y F1174L EGFR G1202R S1206Y KIT G1269A (crizotinib resistant) IGF-1R

G1202R P2Y/PKC F1174C/L (ceritinib resistant) Inadequate central nervous system/brain penetration: G1202R I1171T/N/S (alectinib resistant) Adapted from: Costa DB. Lancet Oncol 2017;18(7):837-839. Costa DB. Cell Cycle. 2017;16(1):19-20. Initial results of the second generation ALK kinase inhibitor alectinib (600 mg twice daily)

- 138 patients with NSCLC received 600 mg/twice day of alectinib;

- Overall response rate (RR) was 50% (95%CI, 41-59);

- The median progression-free survival (PFS) was 8.9 months (95% CI, 5.6-11.3).

- Adverse events were mild (grade 1 or 2) with constipation, fatigue and edema the most common

Ou SH et al. JCO 2016; 34:661 What is the best 1st line ALK TKI for ALK rearranged NSCLC ALEX clinical trial of alectinib vs crizotinib: improved systemic and intracranial control with fewer toxicities

Peters S. et al. NEJM 2017; 377:829-838 The Achilles' heel of oncogene “addicted” tumors

differentiation vascular collapse

survival Driver proliferation oncogene

apoptosis senescence

kinase inhibitor : target EGFR mutations in NSCLC cluster around the tyrosine kinase domain (ATP binding pocket) of EGFR

S768I N-lobe exon 19 T790M deletions/ exon 18 insertions indel C-helix A763_Y764 G719X insFQEA P-loop exon 20 erlotinib insertions L858R L861Q

activation loop

C-lobe

Adapted from Yasuda, Kobayashi, Costa DB. Lancet Oncology; 13(1):e23-31. (2012) Palliative therapies for advanced EGFR mutated NSCLC: (Nov. 2019)

“SM” = sensitizing mutation. “X” in G719X = substitution for several different amino acids and is not a stop codon. Adapted from Sheikine Y, Rangachari D Approved doses of TKIs are: gefitinib 250mg daily, erlotinib 150mg daily (1st generation TKIs); afatinib 40mg daily (2nd et al. Clin Lung Cancer; 17(6):483. generation TKI); osimertinib 80mg daily (3rd generation TKI). #Most common exon 19 deletion is delE746_A750 (LREA (2016) motif). *Cause of acquired resistance to gefitinib, erlotinib and afatinib in >50%. ^Cause of osimertinib resistance in 30%. EGFR TKIs as first line therapy for EGFR mutated NSCLC:

1st/2nd generation EGFR TKIs vs chemotherapy

)

erlotinib

EURTAC (

Summary: (EGFR-L858R and exon 19 deletions)

- ORRs significantly higher for EGFR TKIs

- PFSs were 42-84% longer with EGFR TKIs

- No detriment in OS with EGFR TKIs (cross over)

Gerber D, Gandhi L, Costa DB. Am Soc Clin Oncol Educ Book. (2014) Rossel R., et al. Lancet Oncol;13(3):239 .(2012) Preclinical development of covalent pyrimidine EGFR mutant- specific TKIs and clinical development of the current “evidence- based” first line EGFR TKI osimertinib for common EGFR mutants Head-to-head trials of different EGFR TKIs: 2nd generation (afatinib/dacomitinib) vs 1st generation (gefitinib/erlotinib) 3rd generation (osimertinib) vs 1st generation (gefitinib/erlotinib) Why is osimertinib the current “evidence-based” first line EGFR TKI for common EGFR mutants (FL-AURA trial)? Mechanisms of resistance to covalent pyrimidine EGFR inhibitors such as osimertinib (preclinical models and initial clinical studies of cfDNA/re-biopsy) The future for covalent pyrimidine EGFR inhibitors such as osimertinib: combinations therapies to delay/prevent resistance (↑PFS/OS) What we have learned from the development of EGFR and ALK inhibitors for lung cancers that applies to other oncogene-driven tumors

1. The need to identify an oncogene, its variants, prove in preclinical models that the oncogene drives tumor dependence and can be inhibited with pathway- specific inhibitors, and then develop a clinical test to allow for diagnosis in routine pathology specimens in a timely fashion;

2. The need to prove in clinical trials high response rate, that then can translate into improved outcomes against previously established evidence-based cytotoxic chemotherapy +/- immunotherapy;

3. The need to then develop/test more potent inhibitors (for both systemic disease and central nervous system penetration) and less toxic oral monotherapies that become newest evidence-based backbones for future attempts to improve palliative therapies in advanced disease or be used in the adjuvant setting to attempt to improve cure rates;

4. The understanding that combination therapies to delay/prevent resistance will be part of the clinical trial portfolio for treatment-naïve oncogene-driven tumors within the next decade. Driver oncogene genotypes with kinase inhibitor approval/development (advanced lung adenocarcinoma) in 2019

Genetic aberrations that EGFR mutations can modulate gefitinib/erlotinib targeted or immune afatinib/dacomitinib therapies: osimertinib

differentiation vascular collapse

survival Driver proliferation oncogene

apoptosis senescence

kinase inhibitor : target EGFR or homologous ERBB2 exon 20 insertions mutations cluster near the end of the C-helix within the N-lobe of the kinase, following residue M766 (EGFR)/M774 (ERBB2), but a small subset map to the middle of the C-helix

ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene EGFR (epidermal growth factor receptor) homolog 2)

Adapted from Yasuda et al. Lancet Adapted from: Robichaux JP et al. Nature Med (2018) Oncology; 13(1):e23-31. (2012) http://atlasgeneticsoncology.org/Genes/ERBB2ID162ch17q11.html EGFR exon 20 insertion mutations: Lack of inhibition by 1st/2nd generation EGFR TKIs in vitro All exon 20 mutants, outside A763_Y764insFQEA, are insensitive to 1st/2nd gen. EGFR TKIs N-lobe exon 19 deletions C-helix

762 763 764 765 766 767 768 769 770 771 772 773 774

exon 20 A763_Y764insFQEA Y764_V765insHH M766_A767insAI A767_V768dupASV D770_N771insSVD D770_N771insNPG H773_V774insH exon 18 insertions G719S exon 21 L858R L861Q

loop following C-helix

C-lobe

Yasuda et al. Sci Trans Med. 5:216ra177 (2013) Implications of the crystal structure of a typical EGFR exon 20 insertion: Crystal structure of D770_N771insNPG (insNPG). insNPG may activate EGFR by blocking the conformations required for the inactive conformation of the kinase (i.e., promotes the active conformation). There is no evidence that the insNPG alters interactions with reversible/irreversible EGFR TKIs

Yasuda et al. Sci Trans Med. 5:216ra177 (2013) A C

Clinical experience: lack of response to EGFR TKIs in baseline erlotinib baseline erlotinib (EGFR A763_Y764insFQEA) 150 mg/day (EGFREGFRdelD770insGY)exon 20 mutated150 mg/day NSCLCs B D

All EGFR exon 20 insertion mutated NSCLC, outside A763_Y764insFQEA, were insensitive to reversible EGFR TKIs (gefitinib and erlotinib) in a cohort from BIDMC, DFCI, MGH, MSKCC and NUS baseline erlotinib baseline erlotinib (EGFR A763_Y764insFQEA) 150 mg/day (EGFR delD770insGY) 100 mg/day Best response to reversible EGFR TKI EGFR mutation drug PR SD PD RR [%] A763_Y764insFQEA erlotinib 2 1 - 66.6% Y764_V765insHH gefitinib - 1 - 0% M766_A767insASV erlotinib - - 1 0% A767_V769dupASV gefitinib - - 1 0% V769_D770insASV erlotinib - - 1 0% D770_N771insGL erlotinib - - 2 0% D770_N771insGT erlotinib - - 1 0% D770_N771insSVD erlotinib - 1 1 0% delD770insGY erlotinib - - 2 0% P772_H773insYNP gefitinib - - 1 0% P772_V774insPHV erlotinib - - 1 0% gefitinib/ H773_V774insH - - 2 0% erlotinib H773_V774insNPH erlotinib - - 1 0%

Yasuda et al. Sci Trans Med. 5:216ra177 (2013) Development of novel EGFR exon 20 mutated therapies at MDACC/Yale/NYU: example poziotinib

Adapted from: Robichaux JP et al. Nature Med (2018) Development of novel EGFR exon 20 mutated therapies at DFHCC: example TAK-788 (DFHCC 16-143) Development of novel EGFR inhibitors with broad level of activity, including against EGFR exon 20 insertions: collaboration with Taiho Pharmaceutical Co. Ltd. (Tokyo, Japan) Development of alternative ERBB2 exon 20 mutant therapies: ado-trastuzumab (T-DM1 is an ERBB2-targeted antibody-drug conjugate linking trastuzumab with the antimicrotubule agent emtansine and is an approved medicine for patients with ERBB2-amplified or -overexpressing metastatic breast cancers)

ORR = 44% (95%CI, 22-69%)

Adapted from Li B., J Clin Oncol;36(24):2532-2537 (2018) Palliative therapies for advanced EGFR mutated NSCLC: (Nov. 2019)

“SM” = sensitizing mutation. “X” in G719X = substitution for several different amino acids and is not a stop codon. Adapted from Sheikine Y, Rangachari D Approved doses of TKIs are: gefitinib 250mg daily, erlotinib 150mg daily (1st generation TKIs); afatinib 40mg daily (2nd et al. Clin Lung Cancer; 17(6):483. generation TKI); osimertinib 80mg daily (3rd generation TKI). #Most common exon 19 deletion is delE746_A750 (LREA (2016) motif). *Cause of acquired resistance to gefitinib, erlotinib and afatinib in >50%. ^Cause of osimertinib resistance in 30%. The Achilles' heel of oncogene “addicted” tumors

differentiation vascular collapse

survival Driver proliferation oncogene

apoptosis senescence

kinase inhibitor : target ROS Proto-Oncogene 1, Receptor Tyrosine Kinase (ROS1) is an oncogene in NSCLC: Identification of ROS1 rearrangements/translocations ROS1 rearrangements activate signaling pathways

~ 1-2% of all lung adenocarcinomas ~ 6% of never smokers

Stumpfova M , and Jänne P A Clin Cancer Res 2012;18:4222 One TKI can inhibit multiple tyrosine kinases? (example: crizotinib [multitargeted TKI against MET/ALK/ROS1])

courtesy of Alice Shaw (MGH) + Jorge SE, Costa DB. Lung Cancer 2015:90:369 ROS1 rearrangements define a novel actionable oncogene in NSCLC: preclinical evidence for use of crizotinib

- crizotinib is a multitargeted TKI that has activity against MET/ALK/RON/ROS1

HCC78 H3255 (SLC34A2–ROS1)(EGFR L858R) crizotinib 0 0.1 1.0 0 0.1 1.0 (µM) pROS1

ROS1 70kDa

pAKT

AKT 60kDa

pERK

44kDa ERK 42kDa cell line: actionable (EML4- (SLC34A2- (KRAS) (EGFR actin 45kDa oncogene: ALK) ROS1) L858R)

Adapted from: Yasuda/Costa/Kobayashi J Thorac Oncol. 2012 Jul;7(7):1086-90 ROS1 rearrangements define a novel actionable oncogene in NSCLC: clinical evidence for use of crizotinib

crizotinib 250 mg BID

Bergethon K et al. JCO 2012;30:863-870 ROS1 rearrangements define a novel actionable oncogene in NSCLC: clinical activity of crizotinib (PROFILE 1001 trial) [1]

~ 1-2% of all NSCLC ~ 6% of never smokers sensitive to crizotinib

Stumpfova M , and Jänne P A Clin Cancer Res 2012;18:4222

crizotinib 250 mg BID (PROFILE1001) RR 72% (95%CI 58-84%) [n=50] median PFS 19.2 months (95%CI: 14.4-NR) overall survival (OS) 85% at 12 months

Shaw AT et al. N Engl J Med 2014; 371:1963 ROS1 rearrangements define a novel actionable oncogene in NSCLC: updated results, including overall survival (PROFILE 1001 trial) [2]

ORR = 72% (95% CI, 58% to 83%) Median PFS = 19.3 months (95% CI, 15.2-39.1) Median OS = 51.4 months (95% CI, 29.3 to not reached) 4-year survival rate = 51%

Shaw AT et al. Ann Oncol. 2019;30(7):1121 Mechanisms of resistance to crizotinib in ROS1 rearranged NSCLC

Gainor J et al. JCO Precis Oncol. 2017;2017. More potent ALK/ROS1 TKIs with CNS penetration and activity against some ROS1 crizotinib-resistant mutations (example: lorlatinib)

treatment-naïve prior ROS1 TKI/crizotinib

Shaw A et al. Lancet Oncol. 2019 Oct 25 More potent ROS1/ALK/NTRK TKIs with CNS penetration and activity against some crizotinib-resistant mutations (example: entrectinib)

Among participants with NSCLC harboring ROS1 fusions, entrectinib shrank the tumors of 40 out of 51 (78%) people, including 3 people who had complete responses. For more than half of the people whose tumors shrank, the response lasted for at least 12 months. Drilon A et al. Cancer Discov. 2017:400 https://www.cancer.gov/news-events/cancer-currents-blog/2019/fda- entrectinib-ntrk-fusion ROS1-G2032R may be a clinically-significant crizotinib/lorlatinib/entrectinib-resistant mutation

Katayama R et al. Nat Commun. 2019;10:3604 Lin J. J Thorac Oncol. 2017; 12: 1611 How to select an oral inhibitor for ROS1 rearranged NSCLC? - Crizotinib (FDA approved in 2016): my 1st line choice if no CNS disease Has known/manageable adverse event profile Leads to superb outcomes to control systemic disease (ORR > 70%, mPFS > 19 months, mOS > 50 months) However, the drug has inadequate CNS penetration/activity

- Entrectinib (FDA approved in 2019): my 1st line choice if active CNS disease Adverse event profile is new to most oncologists (CNS effects of cognitive impairment and dizziness) Leads to superb outcomes to control systemic/CNS disease (ORR > 75%, mPFS > ? months, mOS unknown to date) Possible ROS1 resistant mutations overlap with crizotinib

- Lorlatinib (only FDA approved for ALK rearranged lung cancer and not ROS1) Has superb CNS penetration Active against some ROS1crizotinib/entrectinib (S1986X, L2026X, D2033X) mutations NOT active against most common ROS1crizotinib/entrectinib (G2032R) mutation

- Novel/repurposed ROS1 inhibitors with ROS1-G2032R activity (clinical trials) Repotrectinib (TPX-0005), DS-6051b, cabozantinib The Achilles' heel of oncogene “addicted” tumors

differentiation vascular collapse

survival Driver proliferation oncogene

apoptosis senescence

kinase inhibitor : target One TKI can inhibit multiple tyrosine kinases? (example: crizotinib [multitargeted TKI against MET/ALK/ROS1])

courtesy of Alice Shaw (MGH) + Jorge SE, Costa DB. Lung Cancer 2015:90:369 MET amplification as an actionable oncogene in NSCLC responsive to crizotinib - High grade MET amplification present in 1-2% NSCLCs (smokers and never smokers) (adenocarcinoma histology) - Ongoing clinical trials of MET TKIs (example: crizotinib)

Adapted from: Camidge et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8001) Adapted from: Christine Lovly et al. MyCancerGenome.org 2014 MET exon 14 skipping mutations as actionable oncogenes in NSCLC responsive to crizotinib

- MET exon 14 skipping mutations present in 4% NSCLCs (smokers and never smokers) (adenocarcinoma histology)

- Ongoing clinical trials of MET TKIs (example: crizotinib)

TCGA. Nature 511:543 (2014) Kong-Beltran Can Research (2006) Jenkins RW Clin Lung Cancer (2015) Shea M, Costa DB JTO (2016) Updated antitumor activity of crizotinib in patients with MET exon 14-altered advanced non-small-cell lung cancer (PROFILE-1001 MET cohort) IASLC 19th World Conference on Lung Cancer

ORR, 32% (95% CI: 21, 45): n=65 Median DOR was 9.1 mo (95% CI: 6.4, 12.7) Median PFS was 7.3 mo (95% CI: 5.4, 9.1)

Drilon A. Journal of Thoracic Oncology 2018 13, DOI: (10.1016/j.jtho.2018.08.300) Impact of MET inhibitors on survival among patients with non- small cell lung cancer harboring MET exon 14 mutations: a retrospective analysis

overall survival of stage IV METex14 overall survival of stage IV METex14 NSCLC who never received MET TKI NSCLC who received MET TKI/crizotinib

Awad M. Lung Cancer 2019; 133:96 Development of more potent MET inhibitors to target treatment-naïve or crizotinib-resistant METexon14 NSCLC (example: glesatinib)

Engstrom L. Clin Cancer Res; 23(21); 6661 Development of more potent MET inhibitors to target treatment-naïve or crizotinib-resistant METexon14 NSCLC (example:capmatinib) Capmatinib has demonstrated a clinically meaningful response rate and manageable toxicity profile in patients with METΔex14 advanced NSCLC, regardless of the line of therapy

Overall response rate (ORR) by central review: 72% (1st line) 39% (2nd and 3rd line) How to select an oral inhibitor for MET exon 14 skipping mutated NSCLC? - All options are off-label in 2019 - Favor enrollment in clinical trials to help approve an inhibitor

- Crizotinib (only FDA approved for ALK and ROS1 and NOT MET exon 14): Has known/manageable adverse event profile Outcomes to control systemic disease are modest but clinically meaningful (ORR > 30%, mPFS > 7 months, mOS > ? months) However, the drug has inadequate CNS penetration/activity

- Novel/repurposed MET inhibitors with potential activity (clinical trials) Capmatinib Glesatinib Savolitinib Tivantinib Cabozantinib Tepotinib

Foretinib Wang Q. J Hematol Oncol 12, 63 (2019) The Achilles' heel of oncogene “addicted” tumors

differentiation vascular collapse

survival Driver proliferation oncogene

apoptosis senescence

kinase inhibitor : target BRAF mutations as actionable oncogenes in NSCLC

-somatic mutations in BRAF have been found in 1–3% of all NSCLC (smokers and never smokers); (adenocarcinoma histology) - BRAF V600E (~50% of cases)

Adapted from: Planchard et al. J Clin Oncol 31, 2013 (suppl; abstr 8009) Adapted from Christine Lovly et al. MyCancerGenome.org 2013 BRAF mutations as actionable oncogenes in NSCLC Best data with dabrafenib plus trametinib (FDA approval Jun. 2017)

ORR 64% (95% CI: 46-79), n=36 Updates 2019 NCT01336634, n=36: ORR 61.1%, mPFS >10 mths (7.0 to NA), mOS 24.6 mths (11.7 to NA) What about other classes of BRAF mutations and possible mechanisms of resistance to BRAF/MEK inhibitors? Possible resistance mechanisms:

_Truncated BRAF-V600E that promotes inhibitor-insensitive MAPK pathway signaling

_NRAS mutations

_EGFR-mediated RAS-mTOR signaling

_FGFR pathway activation

_Others

Possible clinical management strategies after development of acquired resistance:

_Unclear

_Unknown

Bracht J. Cancers (Basel). 2019; 11(9): 1381 and Okimoto R. PNAS. 2016;113:13456 The Achilles' heel of oncogene “addicted” tumors

differentiation vascular collapse

survival Driver proliferation oncogene

apoptosis senescence

kinase inhibitor : target NTRK 1/2/3 rearrangements across multiple cancers

https://www.ntrktesting.com/NTRK-gene-fusions-in-oncology/ (Bayer) NTRK 1/2/3 rearrangements in NSCLC

- By collating data on 4872 consecutively screened NSCLC cases from unique patients, we estimate a frequency of NTRK fusions in NSCLC of 0.23% (95% CI 0.11-0.40)

- NTRK fusions occur in NSCLCs across genders, ages, smoking histories, and histologies

- Patients with NTRK fusions can respond to targeted TRK inhibition (example entrectinib)

baseline entrectinib entrectinib SQSTM1-NTRK1 day 26 day 155 fusion

Adapted from Farago A. JCO Precis Oncol. 2018 + Farago A. J Thorac Oncol. 2015;10(12):1670 NTRK rearrangements as actionable oncogenes in NSCLCs responsive to potent TRK inhibitors (example entrectinib and larotrectinib) [1]

Adapted from Drilon A. Cancer Discov. 2017:400 + Drilon A. N Engl J Med 2018;378:731 NTRK rearrangements as actionable oncogenes in NSCLCs responsive to potent TRK inhibitors (example entrectinib and larotrectinib) [2] “tissue agnostic” indications On November 26, 2018, the Food and Drug Administration granted accelerated approval to larotrectinib (Vitrakvi, Loxo Oncology Inc. and Bayer) for adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, that are either metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment. Approval was based on data from three multicenter, open-label, single-arm clinical trials: LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431). Efficacy was evaluated in the first 55 patients with unresectable or metastatic solid tumors harboring an NTRK gene fusion enrolled across the three trials. ORR was 75% (95% CI: 61%, 85%). Response duration was 6 months or longer for 73%, 9 months or longer for 63%, and 12 months or longer for 39% of patients. The most common adverse reactions (≥20%) with larotrectinib were fatigue, nausea, dizziness, vomiting, increased AST, cough, increased ALT, constipation, and diarrhea.

On August 15, 2019 the Food and Drug Administration granted accelerated approval to entrectinib (Rozlytrek, Roche) for adults and adolescents aged 12 or older who have solid tumors that harbor a specific genetic alteration. The approval of entrectinib for solid tumors with NTRK gene fusions was based in part on results from three small clinical trials: ALKA-372-001, STARTRK-1, and STARTRK-2. The trials were sponsored by Hoffmann-La Roche, the manufacturer of entrectinib. Trial participants had different types of cancer—mostly sarcoma, lung cancer, and salivary gland cancer—that was either metastatic or locally advanced. NTRK gene fusions were identified by a genetic test. Among the 54 trial participants with NTRK fusions who were included in the analysis, 31 (57%) saw their tumors shrink, including four whose tumors were totally eliminated (a complete response). Among the participants whose tumors shrank, 61% had responses that lasted 9 months or longer. The most serious side effects seen in the four clinical trials, as well as in other studies of entrectinib, were congestive heart failure, central nervous system effects (such as cognitive impairment and dizziness), and bone fractures. The most common side effects were fatigue, constipation, and a distorted sense of taste (dysgeusia). https://www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions-0 https://www.cancer.gov/news-events/cancer-currents-blog/2019/fda-entrectinib-ntrk-fusion The Achilles' heel of oncogene “addicted” tumors

differentiation vascular collapse

survival Driver proliferation oncogene

apoptosis senescence

kinase inhibitor : target RET rearrangements as actionable oncogenes in NSCLC and preclinical rational for use of RET inhibitors

Adapted from Oxnard GR. World Conference Lung Cancer OA12.07 (2018) Adapted from Gainor J. ASCO Annual Meeting 2019 Adapted from Subbiah V. Ann Oncol 2019; 29:1869 RET rearrangements as actionable oncogenes in NSCLC: multi-kinase inhibitors vs selective inhibitors

Adapted from IASLC 2017 and Ackerman et al RET rearrangements as actionable oncogenes in NSCLC responsive to potent RET inhibitors (example selpercatinib/LOXO-292 with FDA breakthrough designation Sep. 2018) [1]

Adapted from Oxnard GR. World Conference Lung Cancer OA12.07 (2018) RET rearrangements as actionable oncogenes in NSCLC responsive to potent RET inhibitors (example selpercatinib/LOXO-292 with FDA breakthrough designation Sep. 2018) [2]

Adapted from Drilon A. WCLC 2019 RET rearrangements as actionable oncogenes in NSCLC responsive to potent RET inhibitors (example pralsetinib/BLU-667 with FDA breakthrough designation 2019)

Adapted from Gainor J. ASCO Annual Meeting 2019 How to select an oral inhibitor for RET rearranged NSCLC?

- Favor enrollment in clinical trials to help approve an inhibitor

- Off-label options of multi-kinase inhibitors have minimal/modest clinical activity: (I don’t recommend using these in routine clinical practice)

Cabozantinib Levantinib Vandetanib Alectinib

- Selective RET inhibitors are promising and ongoing late stages of regulatory approval:

Selpercatinib/LOXO-292 with FDA breakthrough designation 2018

Pralsetinib/BLU-667 with FDA breakthrough designation 2019

(Mechanisms of acquired resistance—on-target or off-target—are not well known) The Achilles' heel of oncogene “addicted” tumors

differentiation vascular collapse

survival Driver proliferation oncogene

apoptosis senescence

kinase inhibitor : target KRAS-G12C mutations as actionable oncogenes in NSCLC and preclinical responses to covalent KRAS G12C inhibitors

KRAS-G12C frequency among different tumor types KRAS-G12C mutations as actionable oncogenes in NSCLC responsive to novel KRAS inhibitors (example AMG510)

Canon J. Nature 2019: 575:217 KRAS-G12C mutations as actionable oncogenes in NSCLC responsive to novel KRAS inhibitors (example MRTX849)

Hallin J. Cancer Discovery 2019 The Achilles' heel of oncogene “addicted” tumors

differentiation vascular collapse

survival Driver proliferation oncogene

apoptosis senescence

kinase inhibitor : target Driver oncogene genotypes with kinase inhibitor approval/development (advanced lung adenocarcinoma) in 2019

Genetic aberrations that EGFR mutations can modulate gefitinib/erlotinib targeted or immune afatinib/dacomitinib therapies: osimertinib

STK11/LKB1 ALK rearrangements TP53 crizotinib/ceritinib alectinib/brigatinib PIK3CA other/ RB1 approved lorlatinib non-targetable ROS1 rearrang. crizotinib/entrectinib HDR genes (BRCA1/2 BRAF-V600E mut. PALB2) dabrafenib + trametinib NTRK rearrang. MSI/MMR larotrectinib/entrectinib genes emerging (MLH1 MET amplification MSH2 MSH6 MET exon 14 other MSI-H) skipping KRAS evolving RET rearrangements Tumor mut. burden mutations (TMB) ERRB2 mutations other possible targetable PD-L1 driver oncogenes KRAS-G12C (FGFR, NRAS, NF1, MAP2K1, BRAF[non-V600E], RIT1) Evidence-based therapies for advanced non-small-cell lung cancer circa 2004 Medical Oncology management of evidence-based therapies for advanced non-small-cell lung cancer from BIDMC – Dec. 2019 Thoracic Oncology Clinic at Beth Israel Deaconess Medical Center: Medical Oncology: Research Scientists: Daniel B. Costa, MD, PhD Daniel B. Costa, MD, PhD Deepa Rangachari, MD Susumu Kobayashi, MD, PhD Meghan Shea, MD (BID-Needham) Daniel G. Tenen, MD Elena Levantini, PhD Thoracic Surgery: Sidharta (Sidhu) Ganghadaran, MD Michael S. Kent, MD / Rona Spector, MD Richard Whyte, MD / Jenn. Wilson, MD / Christian Campos, MD

Interventional Pulmonary: www.bidmc.org/centers-and-departments/cancer-center/cancer-center- Adnan Majid, MD programs-and-services/lung-cancer-program Mihir Parikh, MD / Alex Chee, MD Radiation Oncology: Stuart M. Berman, MD Joseph A. Aronovitz, MD, PhD Pathology: Paul A. VanderLaan, MD RN/NP Coordinator: RN Research: CRAs: Admin. Asst.: Danielle McDonald, RN TBH TBH Andrew Bissaro/ Rena Flambo Contact: 617-667-1901 (phone) 617-667-2518 (fax)