PRACTICE AID in the Treatment of Esophageal, Gastric, and

Immune Checkpoint Inhibition in the Treatment of Esophageal, Gastric, and Colorectal Cancers: Basics and Practicalities

Access the activity, “Evidence and Practicalities: Checkpoint Inhibition in Gastrointestinal Cancers—Translating Recent Advances in Gastric, Esophageal, and Colorectal Cancers,” at PeerView.com/BJU40

PRACTICE AID

CTLA-4 Checkpoint Inhibition

PD-1/PD-L1 Checkpoint Inhibition

PD-1 pathway inhibitssignaling downstream of TCR

• TCR triggered by antigen presented by tumor cell

• Negative regulatory receptor PD-1 expressed and PD-L1 reactively expressed

• PD-L1 binds to PD-1

T cell inactivated

T cell inactivated

T cell activated

T cell activated

Anti–PD-1 or anti–PD-L1monoclonal antibodies

block the interaction and negative regulation

Anti–CTLA-4 monoclonalantibodies block negative

regulation by CTLA-4

CTLA-4 is a negative regulator of costimulation required for

activation of anantitumor T cell in a lymph node upon recognition of

tumor antigens

Anti–CTLA-4 antibody

Anti–PD-1 antibodies

Anti–PD-L1 antibodies

WithoutImmunotherapy

WithImmunotherapy

MHCAntigen

TCR PD-1PD-L1

Anti–PD-L1

Anti–PD-1

Tumorcell

Tumor escape

Inactivationof T Cell

Activationof T Cell

Elimination oftumor cells

WithoutImmunotherapy

WithImmunotherapy

MHC CD80/86

CTLA-4

Anti–CTLA-4antibody

APC

AntigenTCR

Inactivationof T Cell

Activationof T Cell

Tumor escape Elimination oftumor cells

STOP

STOP

GO

GO

Tumor escape

Tumor escape

Tumor attack

Tumor attack

Lymphoid Tissue

Tumor Microenvironment

Ipilimumab

NivolumabPembrolizumab

Cemiplimab-rwlc

AtezolizumabAvelumab

Durvalumab

https://www.PeerView.com/BJU40



PRACTICE AID

Adult and pediatric patients aged ≥12 years with MSI-H/dMMR metastatic colorectal cancer who have progressed

following treatment with fluoropyrimidine, oxaliplatin,

and irinotecan

Adult and pediatric patients with unresectable or metastatic MSI-H/dMMR colorectal cancer who have progressed following treatment with fluoropyrimidine, oxaliplatin,

and irinotecan, or patients with other solid tumors who have progressed following prior treatment and who have no satisfactory alternative treatment options

Patients with recurrent locally advanced or metastatic esophageal squamous cell carcinoma whose tumors express PD-L1 (CPS ≥10, as determined by an FDA-approved test)

with disease progression after ≥1 prior line of systemic therapy

Patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 (CPS ≥1, as determined by an

FDA-approved test) with disease progression on or after ≥2 prior lines of therapy

Adult and pediatric patients aged ≥12 years with MSI-H/dMMR metastatic colorectal cancer who have progressed

following treatment with fluoropyrimidine, oxaliplatin,

and irinotecan

Current Checkpoint Inhibitor Approvals in GI Tract Cancers1

Nivolumab

Pembrolizumab

Emerging Options and New Directions

Nivolumab + Ipilimumab

Nivolumab in previously treated advanced esophageal squamous cell carcinoma regardless of PD-L1 expression (OS benefit vs chemotherapy was seen in the ATTRACTION-3 trial2,3)

Transitioning immunotherapies to earlier lines of therapy, including first-line settings of metastatic disease and early-stage nonmetastatic disease, in esophageal, gastric, and colorectal cancers

Exploring novel immunotherapy-based options and combinations (eg, with targeted agents, antiangiogenics, radiotherapy, and vaccines) in esophageal, gastric, and colorectal cancers




PRACTICE AID

irAEs Associated With Checkpoint Inhibitors: Diagnosis and Management4,5

irAEs

Spectrum of Potential irAEs

Are autoimmune/inflammatory by nature Are different from toxicities from chemotherapies and other cancer therapies Can affect any organ system Can have unpredictable onset (any time during treatment course or after) Can be difficult to differentiate from other causes (diagnosed by exclusion) Treatment depends on severity and may require corticosteroids plus sometimes other

immunosuppressive treatments

More common irAEs• Dermatologic (rash, pruritus, blisters,

ulcers, and vitiligo) • Gastrointestinal (diarrhea, enterocolitis,

transaminitis, hepatitis, and pancreatitis)• Endocrine (thyroiditis, hypophysitis, and

adrenal insufficiency)• Pulmonary (pneumonitis)

Less common irAEs• Hematologic• Cardiovascular• Ocular• Renal• Rheumatic

Musculoskeletal

Gastrointestinal

Renal

Hematologic

Neurologic

Pulmonary

Cardiovascular

Ocular

Dermatologic

Endocrine

Neuropathy, meningitis,Guillain–Barré syndrome,

myasthenia gravis, encephalitis,and transverse myelitis

Myocarditis, pericarditis,arrhythmias, impaired ventricular

function with heart failure andvasculitis, and venous

thromboembolism

Pneumonitis

Colitis, hepatitis, and hepatic transaminases

In�ammatory arthritis, myositis,and polymyalgia-like syndrome

Uveitis/iritis, episcleritis, and blepharitis

Primary hypothyroidism,hyperthyroidism, hypophysitis,primary adrenal insu�ciency,

and diabetes

Rash/in�ammatory dermatitis,bullous dermatoses, and severe

cutaneous adverse reactions

Autoimmune hemolytic anemia,aTTP, hemolytic uremic syndrome,aplastic anemia, lymphopenia, ITP,

and acquired hemophilia

Nephritis




PRACTICE AID

APC: antigen-presenting cell; aTTP: acquired thrombotic thrombocytopenic purpura; CPS: combined positive score; CTLA-4: cytotoxic T-lymphocyte–associated protein 4; dMMR: mismatch repair deficient; irAEs: immune-related adverse events; ITP: immune thrombocytopenia; IVIG: intravenous immunoglobulin; MHC: major histocompatibility complex; MSI-H: microsatellite instability high; PD-1: programmed cell death protein 1; PD-L1: programmed cell death ligand 1; TCR: T-cell receptor.1. https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications. Accessed January 10, 2020. 2. Cho BC et al. European Society for Medical Oncology Congress 2019 (ESMO 2019). Abstract LBA11. 3. Kato K et al. Lancet Oncol. 2019;20:1506-1517. 4. Brahmer JR et al. J Clin Oncol. 2018;36:1714-1768. 5. NCCN Clinical Practice Guidelines in Oncology: Management of Immunotherapy-Related Toxicities. Version 1.2020. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Accessed January 10, 2020.

irAEs Associated With Checkpoint Inhibitors: Diagnosis and Management4,5

Essential Questions to Consider

Grading and General Assessment/Management Recommendations

Continue, suspend, or discontinue checkpoint inhibitor therapy? Use of steroids or other immunosuppressants? Referral to specialists?

Grade Assessment and Management

Grade 1 Asymptomatic; diagnostic changes only • Continue immunotherapy

Grade 2

Mild-to-moderate symptoms; grade 2 diagnostic abnormalities • Hold treatment; provide supportive care • Methylprednisolone 0.5-1.0 mg/kg daily until stable (or oral equivalent)

If improving, transition to oral steroid at start of taper• Prednisone suggested: 60 mg daily for 2 weeks• Taper over ≥4 weeks to reduce recurrence of symptoms • May consider reinitiation of immunotherapy

If progressing, treat as grade 3/4 • Consider hospitalization of patient; perform a multidisciplinary evaluation of toxicity

Grade 3/4Discontinue immunotherapy (consider organ-specific algorithms; endocrine) • Hospitalization indicated • Methylprednisolone 1.0-2.0 mg/kg daily until stable

Refractory

If no improvement or progression, additional immunosuppressant treatment may be needed• Infliximab 5 mg/kg (except if contraindicated)• Mycophenolate mofetil 1 g twice daily • Cyclosporine or IVIG


Maximizing the Potential of Immunotherapies and Combinations in Gastrointestinal Tract Cancers: Key Trials and New Directions


PRACTICE AID

CheckMate -648 (NCT03143153)

1LNivolumab + ipilimumab or nivolumab + cis/5-FU

vs cis/5-FU

Primary EP: OS/PFS in PD-L1+ pts

Active, not recruiting


AdjuvantNivolumab vs placebo

Primary EP: DFSActive, not recruiting

KEYNOTE-590 (NCT03189719)

1L

Pembrolizumab + cis/5-FU vs

placebo + cis/5-FU

Primary EP: OS/PFS in all/PD-L1+ pts


ATTRACTION-05(NCT03006705)

AdjuvantNivolumab + S-1 or

CAPOX vs placebo + S-1 or CAPOX

Primary EP: RFSRecruiting


1LNivolumab + ipilimumab

or nivolumab + CT (CAPOX or FOLFOX) vs CT

Primary EP: OS/PFS in PD-L1+ pts


KEYNOTE-585 (NCT03221426)

Neoadjuvant/adjuvantPembrolizumab +

cis/5-FU vs placebo + cis/5-FU

Primary EP: OS/EFS/pathCR

Recruiting

ATTRACTION-4 (NCT02746796)

1LNivolumab +

SOX/CAPOX vs placebo + SOX/CAPOX

Primary EP: OS/PFS Active, not recruiting

ATOMIC(NCT02912559)

AdjuvantFOLFOX6 with or

without atezolizumab

Primary EP: DFSRecruiting

KEYNOTE-177(NCT02563002)

1LPembrolizumab vs

investigator’s choice of SOC

Primary EP: OS/PFS Active, not recruiting

1L: first line; 2L: second line; 5-FU: 5-fluorouracil; CAPOX: capecitabine plus oxaliplatin; cis: cisplatin; CT: chemotherapy; DFS: disease-free survival; EFS: event-free survival; EP: endpoint; FOLFOX: folinic acid, fluorouracil, oxaliplatin; pathCR: pathological complete response; PD-L1: programmed cell death ligand 1; RFS: relapse-free survival; S-1: tegafur-gimeracil-oteracil potassium; SOC: standard of care; SOX: tegafur-gimeracil-oteracil potassium plus oxaliplatin.1. Cho BC et al. European Society for Medical Oncology Congress 2019 (ESMO 2019). Abstract LBA11. 2. Kato K et al. Lancet Oncol. 2019;20:1506-1517.

A Selection of Phase 3 Checkpoint Inhibitor Clinical Trials in Esophageal, Gastric, and Colorectal Cancers

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ATTRACTION-31,2 (NCT02569242)

2LNivolumab vs

taxane

Primary EP: OSActive, not recruiting

Looking AheadRational combinatorial approaches are being explored

to expand the role and maximize the potential of immunotherapies in gastrointestinal tract cancers:

Checkpoint inhibitors + targeted therapies (eg, cabozantinib, copanlisib, and cobimetinib)

Checkpoint inhibitors + anti-VEGF therapies (eg, regorafenib)

Checkpoint inhibitors + radiation therapy Vaccine-based approaches


Documents

PRACTICE AID in the Treatment of Esophageal, Gastric, and