GI cancers: targeted treatments - PowerPoint Presentation

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GI cancers: targeted treatments and IO approaches for advanced/metastatic disease

Last updated: March 2021

IntroductionThis chapter gives an overview of genetic alterations

associated with selected GI cancers, and summarizes how these may be targeted for the treatment of advanced or metastatic diseaseAlthough chemotherapy regimens represent the standard of care for many GI cancers, targeted options or IO approaches may be considered where biomarker data and/or clinical evidence support their useCRC, colorectal cancer; GI, gastrointestinal; HCC, hepatocellular carcinoma; IO, immunotherapy.

CRC

Gastric

cancer

HCC

Esophageal

cancer

Pancreatic

cancer

Anal

cancer

Overview: targeted therapies and IO approaches for advanced/metastatic GI cancers

Biomarkers to guide treatment selectionTherapeutic targets with approved agentsRole of IOAnti-angiogenic drugs availableCRC1–3

RAS

and

BRAF

mutation status

HER2

amplification status

MSI-h/dMMR statusNTRKEGFRMEKRAFHER2VEGFRNTRKAnti-PD-1/anti-CTLA-4 agents approved as 2L therapy



Gastric cancer4,5

HER2-positive statusPD-L1 expression

MSI-h/dMMR status

HER2VEGFRAnti-PD-1 agent approved for MSI-h/dMMR solid tumorsHCC6-8VEGFR, PDGFR, RAFVEGFR, FGFR, PDGFR, c-KIT, RETc-MET, VEGFR, AXL, RETVEGFR, TIE2, KIT, RET, RAF-1, BRAF, BRAF V600E, PDGFR, FGFR

VEGFR2

Anti-PD-1 agent approved as 2L therapy after failure on RTK-targeted therapy



Esophageal

cancer9–12PD-L1 expressionHER2VEGFR2*Anti-PD-1 agent approved as 2L therapy for advanced ESCC expressing PD-L1Pancreatic cancer13–15None are currently recommended for routine practice(MSI-h/dMMR status and germline BRCA1/2 mutation status may be considered)

EGFR

§PARP

Anti-PD-1 agent approved as 2L therapy for a small subset (1–2%) of MSI-h PDAC tumors



Anal cancer16–18Anti-PD-1 agents may be considered after progression on 1L chemotherapy¶*For EAC or GEJ;8

§The benefit of EGFR-targeted therapy for patients with advanced/metastatic pancreatic cancer may not be clinically meaningful for most patients;

12 ¶Off-label recommendation by NCCN.14 1L, first-line; 2L, second-line; CRC, colorectal cancer; CTLA-4, cytotoxic T-lymphocyte antigen 4; dMMR, mismatch repair deficient; EAC, esophageal adenocarcinoma; EGFR, epidermal growth factor receptor; ESCC,

esophageal squamous cell carcinoma; FGFR, fibroblast growth factor receptor; GEJ, gastroesophageal junction; HCC, hepatocellular carcinoma; HER2, human epidermal growth factor receptor 2; MEK, mitogen-activated protein kinase kinase; MSI-h, microsatellite instability high; NCCN, National Comprehensive Cancer Network; NTRK, neurotrophic tyrosine receptor kinase; PARP, poly adenosine diphosphate ribose polymerase; PDAC, pancreatic ductal adenocarcinoma; PD-1, programmed cell death protein-1; PDGFR, platelet-derived growth factor receptor; PD-L1, programmed death-ligand 1; RTK, receptor tyrosine kinase; VEGFR, vascular endothelial growth factor receptor.

1. Van

Cutsem

E, et al. Ann Oncol 2016;27:1386–422; 2. NCCN Rectal Cancer Guidelines, v1.2021; 3. NCCN Colon Cancer Guidelines, v2.2021; 4. Harada K, et al. F1000Res 2018;7:1365; 5. Smyth EC, et al. Ann Oncol 2016;27:v38–v49; 6. Vogel A, et al. Ann Oncol 2018;29:iv238–iv255; 7. Marrero JA, et al. Clin Liver Dis 2019;13:1; 8. ESMO

eUpdate (June 2020) to Vogel A, et al. Ann Oncol 2018;29:iv238–iv255; 9.

Lordick F, et al. Ann Oncol 2016;27:v50–v57; 10. Bartley AN, et al. J Clin Oncol 2017;35:446–64; 11. Keytruda [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp. February 2019; 12. Ajani JA, et al. J Natl Compr

Canc Netw

2019;17:855–83; 13. Ducreux M, et al. Ann Oncol 2015;26:v56–v68; 14. Orth M, et al. Radiat Oncol 2019;14:141; 15. Golan T, et al. N Engl J Med 2019;381:317–27; 16. NCCN Anal Cancer Guidelines, v1.2020; 17. Symer MM, Yeo HL. F1000Res 2018;7:1572; 18. Glynne-Jones R, et al. Ann Oncol 2014;25:iii10–iii20.

Genetic alterations in GI cancers

Genetic alterations in CRC11. Cancer Genome Atlas Network. Nature 2012;487:330‒7.

Hypermutated (n=30) and non-hypermutated samples (n=165) with complete sequencing data were analyzed separately.CRC, colorectal cancer; PI3K, phosphoinositide 3-kinase; TGFβ, transforming growth factor beta.

Genetic alterations in gastric cancer11. Cancer Genome Atlas Network. Nature 2014;513:202

‒9.Based on primary gastric adenocarcinoma tumor tissue from 295 patients not previously treated with chemotherapy or radiotherapy. Samples were characterized using six molecular platforms.CIN, chromosomal instability; EBV, Epstein–Barr virus; MSI-h, microsatellite instability high.

Based on molecular profiling, four subtypes of gastric cancer have been identified:

1

CIN (50%)

MSI-h (22%)

Genomically stable (20%)

EBV-positive (9%)

Genetic alterations in HCC11. Cancer Genome Atlas Research Network. Cell 2017;169:1327‒41; 2. Vogel A, et al. Ann Oncol 2018;29:iv238–iv255; 3. Marrero JA, et al. Clin Liver Dis 2019;13:1.

Based on whole-exome sequencing on tumor samples from 363 patients with HCC.FGF, fibroblast growth factor; HCC, hepatocellular carcinoma; IO, immunotherapy; RB1, retinoblastoma protein 1; SHH, sonic hedgehog; TGFβ, transforming growth factor beta; VEGF, vascular endothelial growth factor.Dysregulated pathways and processes in HCC:1Wnt, SHH, RAS and p53/RB1 pathways Chromatin modifiers Metabolic reprogramming

Potential therapeutic targets include:

1–3

VEGF and FGF pathways

Wnt pathway

MET pathway

TGF

β pathwayIO approaches

Genetic alterations in esophageal cancer1

1. Cancer Genome Atlas Research Network. Nature 2017;541:169‒75. Based on an integrated molecular analysis of 164 esophageal carcinomas.EAC, esophageal adenocarcinoma; ESCC, esophageal squamous cell carcinoma; PI3K, phosphoinositide 3-kinase.

ARID1A, SMARCA4, KDM6A, KMT2D

GATA4, GATA6, TP63/SOX2, NOTCH1, ZNF750

MYC, SMAD4, SMAD2, FBXW7, APC, CTNNB1, PTCH1

CDKN2A, CCND1, CDK6, CCNE1, RB1

ERBB2, VEGFA, EGF

R, KRAS, IGF1R,

PTEN, PIK3R1, MET, PIK3CA, FGFR1, FGFR2Altered genes

Genetic alterations in pancreatic cancer1 1. Cancer Genome Atlas Research Network. Cancer Cell 2017;32:185‒203

.Based on an integrated genomic analysis of 149 non-hypermutated PDAC samples. Genes mutated in <5% of samples have been omitted.HER2, human epidermal growth factor receptor 2; PDAC, pancreatic ductal adenocarcinoma.

RAS pathway activation is a prominent oncogenic driver in PDAC:

1

93% of tumors harbor a

KRAS

mutation

Some tumors harbor multiple

KRAS mutationsEven in KRAS wild-type tumors, other alterations (such as BRAF mutation or HER2 amplification) result in RAS pathway activation

Genetic alterations in anal cancer11. Morris V, et al. Mol Cancer Res 2017;15:1542‒50.

Based on a pooled mutation analysis of 17 patients (measured in a 263-gene panel) and 24 patients (by whole-exome sequencing) with SCCA.HPV, human papillomavirus; MAPK, mitogen-activated protein kinase kinase; SCCA, squamous cell carcinoma of the anal canal.

In this analysis,

PIK3CA

was mutated in 29% of patients, and amplified in more than two-thirds of cases, suggesting that up to 90% of SCCA tumors may have some form of

PIK3CA

alteration

1MAPK pathway-related alterations were relatively rare, consistent with other HPV-positive squamous cancers1Routine testing for RAS/RAF mutations is therefore unlikely to impact clinical decision making for advanced/metastatic disease

1

Treatment considerations for advanced/metastatic GI cancersTargeted treatments and IO approaches

DisclaimerThe following information on treatment considerations is given for educational purposes only and is neither complete nor conclusive. It should

should not be construed as medical guidance or guidance from Boehringer IngelheimThe information was compiled with the greatest care; nevertheless, no responsibility is assumed for representing every possible detail that may be relevant to each individual caseApproved indications may vary between countries. You should take into consideration all relevant sources of information when making treatment decisions, in particular your local guidelines and Prescribing Information/Summary of Product CharacteristicsAll treatment decisions rest solely with the treating healthcare professional. Please note that there may be new findings not reflected in this document (as of March 2021)

Treatment considerations for advanced/metastatic CRC*RAS

and BRAF testing is recommended for all patients at the time of diagnosis of metastatic CRC. Note that BRAF mutations (most frequently V600E) are almost exclusively non-overlapping with RAS mutations1For KRAS/NRAS/BRAF wild-type CRC, irinotecan/oxaliplatin-based chemotherapy combined with an EGFR-targeted agent is an approved treatment option2,3For BRAF V600E CRC, irinotecan + EGFR- and RAF-targeted agents, or combination treatment with MEK-, RAF- and EGFR-targeted agents, are approved treatment options2,3Other molecular targets may help guide treatment selection:2,3For HER2-amplified, RAS

wild-type metastatic CRC,

HER2-targeted therapy

is an option

For MSI-h/dMMR CRC, treatment with a

PD-1 ± CTLA-4

regimen may be an option

For NTRK fusions, treatment with larotrectinib and entrectinib is an optionAnti-VEGF-targeted agents may be considered in combination with chemotherapy in patients with metastatic CRC; however, there are no validated biomarkers available to guide their selection1Wnt/β-catenin, TGFβ, EGFR-RAS-MAPK and p53 pathways are areas of active, ongoing research for advanced CRC4,51. Van Cutsem E, et al. Ann Oncol 2016;27:1386–422; 2. NCCN Rectal Cancer Guidelines, v1.2021; 3. NCCN Colon Cancer Guidelines, v2.2021; 4. Cheng J, et al. Cancer Res 2018;78:5072–83; 5. Koveitypour Z, et al. Cell Biosci 2019;9:97.*The safety profile and efficacy of treatment options is not presented here; please refer to the relevant Prescribing Information/Summary of Product Characteristics and published clinical data for more details.CRC, colorectal cancer; CTLA-4, cytotoxic T-lymphocyte antigen 4; dMMR, mismatch repair deficient; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; MSI-h, microsatellite instability high; PD-1, programmed cell death protein-1; TGFβ, transforming growth factor beta; VEGF, vascular endothelial growth factor.

Treatment considerations for advanced/metastatic gastric cancer*

For locally advanced disease, targeted therapies are not recommended, irrespective of setting (neo-adjuvant, peri-operative or adjuvant settings)1For metastatic disease, there are few approved targeted therapy options and outcomes are poor, with median survival typically <12 months1First-line treatment: For confirmed HER2-positive tumors (10–15% of cases), the addition of trastuzumab to cytotoxic therapy may be considered1,2For HER2-negative disease, no targeted therapy is currently approved, and doublet therapy with oxaliplatin (preferred) or cisplatin plus 5-FU or capecitabine is recommended. Potential triplet combinations (depending on tolerability) include: addition of an anthracycline to a platinum and FP doublet; taxane-containing triplets (e.g. DCF, FLOT); or FOLFIRI1,2Second-line treatment and beyond:

Chemotherapy with a taxane (docetaxel or paclitaxel), or irinotecan, or

ramucirumab (monotherapy or combined with paclitaxel)

are recommended for fit patients

1,2

For PD-L1-expressing or MSI-h/

dMMR

tumors, anti-PD-1-targeted treatment is an approved option1Chemotherapy with trifluridine/tipiracil is an option for patients with metastatic/advanced gastric cancer and performance status 0–13Other targeted therapies (e.g. agents targeting MET, mTOR, FGFR or PARP) have not yet demonstrated clinical benefit in advanced gastric cancer1,21. Harada K, et al. F1000Res 2018;7:1365; 2. Smyth EC, et al. Ann Oncol 2016;27:v38–v49; 3. ESMO eUpdate (Nov 2019) to Smyth EC, et al. Ann Oncol 2016;27(Suppl 5):v38–v49.*The safety profile and efficacy of treatment options is not presented here; please refer to the relevant Prescribing Information/Summary of Product Characteristics and published clinical data for more details. 5-FU, fluorouracil; DCF, 3-weekly docetaxel, 5-FU and cisplatin; dMMR, mismatch repair deficient; FGFR, fibroblast growth factor receptor; FLOT, fluorouracil, leucovorin, oxaliplatin and docetaxel; FOLFIRI; irinotecan plus leucovorin and 5-FU; HER2, human epidermal growth factor receptor 2; MSI-h, microsatellite instability high; mTOR, mammalian target of rapamycin; PARP, poly adenosine diphosphate ribose polymerase; PD-1, programmed cell death protein-1; PD-L1, programmed death-ligand 1.

Treatment considerations for advanced/metastatic HCC*Although many of the available treatments are receptor-targeted small-molecule inhibitors,

molecular profiling is not recommended as standard practice for advanced HCC, since it currently has no direct implication on clinical decision making1For first-line treatment:1,2 Sorafenib (multikinase inhibitor, including VEGFR2 and BRAF) is the standard of careLenvatinib (multikinase inhibitor, including VEGFR1–3 and FGFR1–4) is also an optionAtezolizumab (anti-PD-L1 antibody) plus bevacizumab (anti-VEGF antibody) is another option3For second-line treatment:1,2,4Regorafenib (multikinase inhibitor related to sorafenib) is approved after progression on sorafenibCabozantinib (MET, VEGFR2, AXL and RET inhibitor) may be considered after progression on one or two systemic therapiesRamucirumab (anti-VEGFR2 antibody) is an option for patients with AFP ≥400 ng/mLNivolumab (anti-PD1 antibody) may be considered after progression on RTKsPembrolizumab (anti-PD1 antibody) may be used for patients who have been previously treated with sorafenib51. Vogel A, et al. Ann Oncol 2018;29:iv238–iv255; 2. ESMO eUpdate (June 2020) to

Vogel A, et al. Ann Oncol 2018;29:iv238–iv255

; 3. Finn RS, et al. N

Engl

J Med 2020;382(20):1894–905; 4.

Marrero JA, et al. Clin Liver Dis 2019;13:1; 5. Keytruda [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp. February 2019.

*The safety profile and efficacy of treatment options is not presented here; please refer to the relevant Prescribing Information/Summary of Product Characteristics and published clinical data for more details.

AFP, alpha-fetoprotein; FGFR, fibroblast growth factor receptor; HCC, hepatocellular carcinoma; RTK, receptor tyrosine kinase; VEGFR, vascular endothelial growth factor receptor.

Treatment considerations for advanced/metastatic esophageal cancer*Targeted therapy options for advanced

esophageal cancer (either EAC or ESCC) are limited; treatment options typically include chemotherapy or palliative care1Treatment of esophageal cancer may differ depending on histopathology and local guidelines:ESMO guidelines recommend that advanced esophageal adenocarcinoma (including GEJ adenocarcinoma) is treated in the same way as advanced gastric cancer1Molecular testing may be used to select patients with HER2-positive, advanced lower esophageal/gastric cancer for treatment with a trastuzumab-based regimen1 Nivolumab is also approved for patients with ESCC that have progressed on fluoropyrimidine- and platinum-based combination chemotherapy2NCCN guidelines also suggest treating patients with advanced, HER2-positive gastroesophageal adenocarcinoma with trastuzumab-based therapy3 Second-line treatments include combination ramucirumab/paclitaxel for esophageal and GEJ adenocarcinoma, nivolumab for ESCC, and pembrolizumab for advanced ESCC expressing

PD-L1 after failure of ≥1 line of prior systemic therapy

3

1.

Lordick F, et al. Ann Oncol 2016;27:v50–v57

; 2.

Opdivo

[package insert]. Princeton, NJ: Bristol-Myers Squibb. December 2020; 3. NCCN Esophageal Cancer Guidelines, v1.2021.*The safety profile and efficacy of treatment options is not presented here; please refer to the relevant Prescribing Information/Summary of Product Characteristics and published clinical data for more details. EAC, esophageal adenocarcinoma; ESCC, esophageal squamous cell carcinoma; GEJ, gastroesophageal junction; HER2, human epidermal growth factor receptor 2; NCCN, National Comprehensive Cancer Network; PD-L1, programmed death-ligand 1.

Treatment considerations for advanced/metastatic pancreatic cancer*Targeted treatment options are extremely limited

; treatment options are centered around FOLFIRINOX, gemcitabine (monotherapy or combinations) or supportive care, depending on patients’ functional status1Treatment outcomes are poor, with median OS of <1 year1In a clinical study, the addition of the EGFR-targeted agent erlotinib to gemcitabine achieved a modest OS improvement of 12 days vs gemcitabine alone, which does not support widespread use in most patients1For a small subset of patients with MSI-h or dMMR PDAC (~1–2%), pembrolizumab may be an effective second-line treatment option2–5The complexity and instability of PDAC and the dense, heterogeneous nature of the TME make targeted therapy a challenging prospect6RAS–RAF–MEK–ERK pathway inhibition is of interest due to the high prevalence of related alterations1,6PARP inhibitors (e.g. olaparib) are of interest for the ~4.6% of patients with BRCA-mutated, advanced PDAC4,7

Other strategies include targeting TGFβ, hedgehog or

Wnt

signaling

pathways

3

1. Ducreux M, et al. Ann Oncol 2015;26:v56–v68; 2. Orth M, et al. Radiat Oncol 2019;14:141; 3. Hilmi M, et al. World J Gastroenterol 2018;24:2137–51; 4. Sohal DPS, et al. J Clin Oncol 2018;36:2545–56; 5. Hu ZI, et al. Clin Cancer Res 2018;15;24(6):1326–36; 6. Aslan M, et al. Anticancer Res 2018;38:6591–606; 7. NCCN Pancreatic Adenocarcinoma Guidelines, v1.2021. *The safety profile and efficacy of treatment options is not presented here; please refer to the relevant Prescribing Information/Summary of Product Characteristics and published clinical data for more details. dMMR, mismatch repair deficiency; EGFR, epidermal growth factor receptor; ERK, extracellular signal-related kinase; FOLFIRINOX, folinic acid, fluorouracil, irinotecan and oxaliplatin combination chemotherapy; MEK, mitogen-activated protein kinase kinase; MSI-h, microsatellite instability high; OS, overall survival; PARP, poly adenosine diphosphate ribose polymerase; PDAC, pancreatic ductal adenocarcinoma; TGFβ, transforming growth factor beta; TME, tumor microenvironment.

Treatment considerations for advanced/metastatic anal cancer*There is a

lack of available targeted therapy options for patients with advanced/metastatic SCCA1For most patients, cytotoxic chemotherapy and radiotherapy are the mainstays of treatment1For first-line treatment of metastatic SCCA, treatment with carboplatin/paclitaxel is preferred, according to NCCN guidelines2Palliative radiotherapy can be administered with chemotherapy for local control of symptomatic bulky diseaseAfter progression on first-line chemotherapy, nivolumab or pembrolizumab may be considered2Future treatment strategies may include therapeutic vaccination to raise an immunologic response,1 or other IO-based approaches1. Symer MM, Yeo HL. F1000Res 2018;7:1572; 2. NCCN Anal Carcinoma Guidelines, v1.2021.*The safety profile and efficacy of treatment options is not presented here; please refer to the relevant Prescribing Information/Summary of Product Characteristics and published clinical data for more details. IO, immunotherapy; NCCN, National Comprehensive Cancer Network; SCCA, squamous cell carcinoma of the anal canal.

Summary

SummaryMolecular characterization of GI cancers reveals a wide range of potentially targetable alterations

For the most common GI cancers, such as CRC, several targeted treatment options are available for locally advanced/metastatic disease; treatment selection is often based on the results of biomarker testing, and is robustly supported by clinical dataFor less common cancers, such as pancreatic and anal cancers, fewer to no approved targeted options are available; management is typically based around chemotherapy and supportive care, although IO approaches may also be an option for some patientsCancer’s ‘big four’ (KRAS, p53, β-catenin and MYC) are among the most frequently mutated oncogenic drivers in GI cancers. Successfully targeting these pathways could address a significant unmet need for many patients with advanced/metastatic diseaseMolecular analysis highlights the importance of growth, proliferation and survival pathways (such as Wnt/β-catenin, RAS/RAF/MEK/ERK, p53, MYC, PI3K, TGFβ and mTOR) in many GI cancersOther potential therapeutic targets include DNA damage repair pathways, epigenetic regulation and metabolic processing pathwaysIntelligent combinations of targeted agents with IO therapies could act synergistically to maximize the impact of future treatments for GI cancersCRC, colorectal cancer; ERK, extracellular signal-related kinase; GI, gastrointestinal; IO, immunotherapy; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase; TGFβ, transforming growth factor beta.