Targeted Therapies: Side effects and management

William Tew, MDAssociate Attending

Clinical Director, Gynecologic Medical OncologyMemorial Sloan Kettering Cancer Center, NY

VERBAL DISCLOSURE• No conflicts to disclose.

Ovarian Cancer Type as a Biomarker

High Grade Serous Clear Cell Endometrioid Mucinous Low Grade Serous

Genetic Risk Factors

BRCA 1/2 HNPCC HNPCC None known None known

Precursor Lesion Serous Tubal Intraepithelial Carcinoma

(STIC)

Endometriosis Endometriosis Unknown?Teratoma

Serous Borderline Tumor

Molecular Genetics

p53, BRCA, HR Defects,

Tumor Microenvironment

PI3K, ARID1A, MSI PTEN, beta-catenin, ARID1A, MSI

KRAS, HER2 BRAF, KRAS, NRAS

Potential Drugs •PARP inhibitors•Angiogenesis

•mTor•Angiogenesis

- •Trastuzumab•TDM-1

•MEKi•Angiogenesis

J Natl Cancer Inst 2014;106(4):1-8

Ovarian Cancer TherapiesFDA Approved1978 Cisplatin1990 Altretamine1991 Carboplatin1992 Paclitaxel1996 Topotecan2000 Pegylated liposomal doxorubicin (PLD)2006 Gemcitabine + Carboplatin2014 Bevacizumab – platinum resistant(+weekly paclitaxel, PLD or topotecan)2014 Olaparib2016 Bevacizumab – platinum sensitive(+paclitaxel/carboplatin; gemcitabine/carboplatin)2016 Rucaparib 2017 Niraparib/Olaparib – 2nd remission

NCCN 1 or 2A• Capecitabine• Cyclophosphamide• Docetaxel• Doxorubicin• Etoposide (oral)• Ifosfamide• Irinotecan• Melphalan• Oxaliplatin• Paclitaxel, albumin bound (nab-paclitaxel)• Pemetrexed• Vinorelbine

TCGA

BRCA1 Germline

8%BRCA2

Germline6%

BRCA1 Somatic4%

BRCA2 Somatic3%

BRCA1 Methylation

11%

EMSY Amplification

6%PTEN Loss

6%Other HRD5%

CCNE1 Amplification

14%RB1 Loss4%

MMR Germline

2%

Other31%

HRDNot HRD

Mutually exclusive events

cBio Cancer Genomics Portal, MSKCC

BRCA1Germline,

8%

BRCA2Germline, 6%

BRCA1Soma c, 4%

BRCA2Soma c,3%

BRCA1Methyla on,

11%

PTENLoss, 6%Other HRD,

10%

CCNE1Amplifica on,

20%

RB1Loss, 15%

NF1Loss, 17%

HRDNot HRD

Putative driver events

cBio Cancer Genomics Portal, MSKCC and Patch et al., Nature, 2015

Targeted therapies: Toxicity • Immunotherapy• PARP inhibitors• VEGF inhibition

Harnessing the Power of the Immune System

How does the immune system recognize tumor as non-self?

Kerkar SP , Restifo NP Cancer Res 2012;72:3125-3130

Tumors are not just composed of cancer cells

Immunotherapy toxicities: Diverse• Cancer vaccines – injection site rxn and

constitutional symptoms• Cytokines – induce capillary leak• Adoptive cell therapy – cytopenias (prep chemo),

cytokine release syndrome and autoimmunity• T-cell regulation via immunomodulatory Ab….

Weber et al, JCO 2015

Immunomodulatory antibodies that regulate T cell activity

Turning up The Activating Blocking the InhibitingSlides courtesy of Drs. Dmitriy Zamarin and Alex Snyder

FDA Approved Targets

Turning up The Activating Blocking the Inhibiting

Year Drug Target Disease Indication

2011 Ipilimumab CTLA-4 Melanoma

2014 Nivolumab, pembrolizumab

PD-1 Melanoma

2015 Nivolumab, pembrolizumab

PD-1 NSCLC

2015 Nivolumab PD-1 RCC

2015 Nivolumab+ipilimumab PD-1 + CTLA4 Melanoma

2015 Pembrolizumab PD-1 Head and Neck SqCC

2016 Nivolumab PD-1 Hodgkin lymphoma

2016 Atezolizumab PDL-1 Urothelial cancer

2017? Anti-PD-1 MMR-deficient cancers

Current FDA Approvals: Checkpoint Inhibitors

*as of 10/30/2016

Nivolumab (Opdivo, BMS); Pembrolizumab (Keytruda, Merck); Atezolizumab (Tecentriq, Roche); Ipilimumab (Yervoy, BMS)

Checkpoint Inhibitors Toxicities• Result from inappropriate recognition of normal tissues by T cells, leading

to autoimmune tissue destruction. • Side effects are generally mild and infrequent, but when they do occur,

they can be serious and even life threatening if not identified and treated in a timely manner. Early recognition and treatment is essential.

• Need to be distinguished from other causes, especially infectious causes or underlying disease

• Toxicities can be long-lasting, even after therapy discontinuation. Some toxicities appear after therapy discontinuation.

• Some toxicities are irreversible (i.e. hypothyroidism, adrenal insufficiency) and require long-term monitoring

Immunotherapy toxicitiesOccasional:•Fatigue, headaches, arthralgia, fever, chills•Skin: rash•Asymptomatic lab abnormalities: elevation of LFT’s, amylase/lipase•GI: colitis, pancreatitis, hepatitis•Endocrine: thyroiditis, hypothyroidism, hypophysitis, hypoadrenalism

Rare:•Pulmonary: pneumonitis

Very Rare:•Other organs: kidneys, CNS, muscle, heart, bone marrow•Cytokine release syndrome: fever, hypotension, pulmonary edema, multi-organ failure. Can mimic sepsis.

Kinetics of Appearance of irAEs

Weber et al. JCO 2012

General guidelines:• Low grade toxicities (grade 1-2): observe, hold drug, topical steroids

( Rash – topical hydrocortisone; Diarrhea – budesonide)

• Medium grade toxicities (grade 2-3): hold, oral systemic steroids (prednisone, methylprednisolone), closer monitoring

• High grade toxicities (grade 3-4): admit, IV steroids

• Steroid-refractory toxicities: other immunosuppressant agents (Mycophenolate Mofetil for liver toxicity; Infliximab for other toxicities)

Toxicity Guidelines (non-protocol)• On-line safety tools

– https://www.opdivosafetytool.com

• Multidisciplinary expert panel guidelines – “Management of Immunotherapy Side Effects”– American Society of Clinical Oncology (ASCO) and the National

Comprehensive Cancer Network® (NCCN®) joint collaboration

Examples of management protocol algorithms (BMS)

Immune-related Adverse Events (irAE)

Pro

port

ion

of

Aff

ecte

d P

atie

nts

Rash/pruritus

PneumonitisMyocarditis, rare neurologic syndromes*, cholangitis*, vasculitis neuropathy*, atrophic exocrine pancreatic

insufficiency*, sclerodermoid reaction*, others…

Figure legend: Approximate proportion of patients affected by immune-related adverse events of any grade upon treatment with single-agent PD-1 blockade.

Endocrinopathies, arthralgia

20%

Diarrhea

Friedman and Snyder, Annals of Oncology, 2017

Rare Side Toxicities: Long Tail of irAE

Results on ECG and Immune Effects in Cardiac Muscle after Treatment with Ipilimumab and Nivolumab

Johnson DB et al. N Engl J Med 2016;375:1749-1755

Immunotherapy in Older adults: FDA experience

Singh et al, FDA subset analysis of the safety of nivolumab in elderly patients with advanced cancers. J Clin Oncol 34, 2016 (suppl; abstr 10010)

- irAE rates similar across age group.- Look at other parameters (which do increase with age)

- drug discontinuation - intervention required

Weber, Immunotherapy: It's Not Getting Old, ASCO 2016

Toxicity • Immunotherapy• PARP inhibitors• VEGF inhibition

FDA approved PARP inhibitorsTreatment

Approval date Rx Indication Data

Olaparib 12/2014 400 mg BID (50 mg CAPSULES)

Deleterious germline BRCA mut ≥3 more priors

Study 42

Rucaparib 12/2016 600 mg BID (200 mg, 300 mg capsules)

Deleterious germline OR somatic BRCA mutation &≥2 more priors

Study 10, ARIEL2

Maintenance

Niraparib 3/2017 300 mg daily (100 mg capsules)

Recurrent ovarian cancer &complete or partial response to platinum based chemotherapy

NOVA

Olaparib 8/2017 300mg BID(150mg, 100mg TABLETS)

Recurrent ovarian cancer &complete or partial response to platinum based chemotherapy

SOLO-2Study 19

Each PARP inhibitor has DIFFERENT properties/indication…PARP inhibitor CYP enzymes used for

metabolismDrug Drug Interactions Effect on renal and hepatic uptake

transporters

Rucaparib1 CYP2D6 (predominant)

CYP1A2 and CYP3A4 (lesser extent)

Reversibly inhibits CYP1A2, CYP2C19, CYP2C9, CYP3AInduces CYP1A2

Inhibits MATE1 and MATE2-K (potent), OCT1 (moderate)

Olaparib1 CYP3A4* Inhibits CYP3A4 and induces CYP2B6

Inhibits OATP1B1, OCT1, OCT2, OAT3, MATE1, MATE2K

Niraparib2 CYP3A4/5 and CYP1A2

CYP2D6 (lesser extent) Amide hydrolysis is main hepatic clearance

Can induce CYP1A2 (weak)

No interaction with the major hepatic or renal uptake transporters

1FDA package inserts2niraparib IB

*Reduce dose if strong or moderate CYP3A inhibitorsare co-administered

Slides courtesy of Dr. Ursula Matulonis

GI toxicities are common with all PARP inhibitorsToxicities (%) Grade of Tox Olaparib 1 Rucaparib2 Niraparib3

Nausea All Grades 64 77 73.6

Grade 3 and 4 3 5 3.0

Constipation All 20.65 40 39.8

Grades 3 and 4 0 2 0.5

Vomiting All 43 46 34.3

Grades 3 and 4 4 4 1.9

Decreased appetite All 22 39 25.3

Grades 3 and 4 1 3 0.3

Abdominal pain All 43 32 22.6

Grades 3 and 4 8 3 1.1

Diarrhea All 31 34 19.1

Grades 3 and 4 1 2 0.3

Dyspepsia All 25 104 11.4

Grades 3 and 4 0 <1% 0

Dysgeusia All 215 39 10.1

Grades 3 and 4 0 0.3 0

1FDA insert, 2FDA insert, 3NOVA NEJM 2016, 4Swisher Lancet Onc 2016, 5Ledermann Lancet Oncology 2014

Fatigue is common with all PARP inhibitors

Toxicities (%) Grade of Tox Olaparib 1 Rucaparib2 Niraparib3

Fatigue All Grades 66 77 59.4%

Grade 3 and 4 8 11 8.2%

Insomnia All NR 12% 24.3%

Grades 3 and 4 NR 0 0.3%

Headaches All Grades 255 174 25.9

Grades 3 and 4 0 04 0.3

1FDA insert, 2FDA insert, 3NOVA NEJM 2016, 4Swisher Lancet Onc 2016 5Ledermann Lancet Oncology 2014

Hematologic toxicities

Toxicities Grade of Tox Olaparib1 Rucaparib2 Niraparib3

Decrease in hemoglobin All Grades 90 67 50.1

Grade 3 and 4 15 23 25.3

Decrease in platelets All 30 39 61.3

Grades 3 and 4 3 6 33.8

Decrease in neutrophil count

All 25 35 30.2

Grades 3 and 4 7 10 19.6

1FDA package insert, 2FDA package insert, 3NOVA NEJM 2016

(% of pts)

Additional toxicities differ between agents

Toxicities Grade of Tox Olaparib1 Rucaparib2 Niraparib3

Increased Creatinine All 30 92% NR

Grades 3 and 4 2 1 NR

Elevated ALT All NR 74% NR

Grades 3 and 4 NR 13% NR

Elevated AST All NR 73% NR

Grades 3 and 4 NR 5% NR

Hypertension All NR NR 19.3%

Grades 3 and 4 NR NR 8.2%

Nasopharyngitis/URI All 26 104 11.2

Grades 3 and 4 0 04 0

Dyspnea All NR 21 19.3

Grades 3 and 4 NR 0.5 1.1

Palpitations All NR NR 10.4

Grades 3 and 4 NR NR 0

1FDA insert, 2FDA insert, 3NOVA NEJM 2016, 4Swisher Lancet Onc 2016 5Ledermann Lancet Oncology 2014

(% of pts)

Other side effects…• Pneumonitis

reported in <1% of pts treated with olaparib• AML/MDS (leukemia, pre-leukemia)

OLAP 0.8% (22/2618)1

Rucaparib 0.5% (2/377)2

Niraparib 1.4% (5/367)3 • Increase in cholesterol

Rucaparib2: 40% all grades; 2% grade 3 and 4• Rash/photosensitivity reaction

Rucaparib: 15%/10% Olaparib: 25%/0

1FDA insert, 2FDA insert, 3NOVA NEJM 2016,

Toxicity • Immunotherapy• PARP inhibitors• VEGF inhibition

Tumor Angiogenesis and Cancer Treatment

Blood vessel

Tumor that can grow and spreadSmall localized tumor

Signaling molecule

Angiogenesis

AURELIA: Bevacizumab for Platinum-Resistant Ovarian Cancer.

Stratification factors:

•Chemotherapy selected

•Prior anti-angiogenic therapy

•Treatment-free interval (PFI <3 vs 3 6 months)‒

Platinum-resistant

•≤2 prior regimens

•No history of bowel obstruction/fistula, or clinical/radiological evidence of rectosigmoid involvement

Treat to PD/toxicity

Treat to PD/toxicity

Investigator’s choice

(without BEV)

Optional BEV monotherapy^

BEV 15 mg/kg q3w*

+ chemotherapy

Chemotherapy

R

1:1

Chemotherapy options (investigator’s choice):

•Paclitaxel 80 mg/m2 days 1, 8, 15 & 22 q4w

•Topotecan 4 mg/m2 days 1, 8 & 15 q4w (or 1.25 mg/m2, days 1–5 q3w)

•PLD 40 mg/m2 day 1 q4w*Or 10 mg/kg q2w^15 mg/kg q3w, permitted on clear evidence of progression

J Clin Oncol 2014;32(13):1302-8

AURELIA

RR Chemo alone

RR Chemo + Bev

Median PFS Chemo alone

(months)

Median PFS Chemo + Bev

(months)

HR Median OSChemo Alone

(months)

Median OS Chemo + Bev

(months)

HR

Overall Study 11.8% 27.3% 3.4 6.7 0.48(0.38-0.60)

13.3 16.6 0.85(0.66-1.08)

Paclitaxel 30.2% 53.3% 3.9 10.4 0.46 (0.30-0.71)

13.2 22.4 0.65 (0.42-1.02)

PLD 7.8% 13.7% 3.5 5.4 0.57 (0.39-0.83)

14.1 13.7 0.91(0.62-1.36)

Topotecan 0% 17% 2.1 5.8 0.32 (0.21-0.49)

13.3 13.8 1.09(0.72-1.67)

J Clin Oncol 2014;32(13):1302-8; J Clin Oncol 2015;33:3836-3838

HFS = hand-foot syndromeaPreferred terms. bIncludes abdominal pain upper

Patie

nts

(%)

Periphera

l senso

ry

neuropath

y

Abdominal pain

b

≈≈≈

≈

0

2

4

6

8

10

12

14

16

18CT (n=181)

BEV + CT (n=179)

J Clin Oncol 2014;32(13):1302-8

AURELIA: Side effects with addition of Bev to chemotherapy

Older adults: Bevacizumab increases Grade 3-5 toxicity

Mohile, Tew et al. The Oncologist 2013;18:408-414©2013 by AlphaMed Press

Bevacizumab: - Hypertension- Bleed- Clots (arterial, venous)- Proteinuria- Bowel perforation

Phase II: Olaparib (PARPinh)+ Cediranib (Angiogenesis)• Platinum-sensitive recurrent ovarian cancer• Median PFS improvement in combo (17.7 vs. 9months)• High toxicity, mostly cediranib related:

– Grade 3-5 AEs (70%): fatigue, diarrhea, and hypertension.– Drug dose reduction (77%): mostly cediranib

• Fit, young pt population:– Median age 58 (42-86)– ECOG PS 0 (71%)– ECOG PS 1 (29%)

• NRG studies:– Platinum Sensitive– Platinum Resistant

Liu et al, Lancet Oncol, 2015

Financial Toxicity

Summary• Targeted agents bring unique, yet often manageable side

effects.

• Special attention to drug combinations and populations not studied in prospective studies (elderly)

• With a FDA indication and broader use, very rare side effects can be discovered.