Fall Summit | October 18-20 | Orlando, FL
Sarah Peters, PharmD, MPH, BCOP, Associate Professor, Pharmacy Practice, Albany College of Pharmacy and Health
Sciences
What's New in Oral Chemotherapy
What’s new with Oral Chemotherapy? NATIONAL COMMUNITY ONCOLOGY DISPENSING ASSOCIATION NATIONAL SUMM IT
OC TOBER 20, 2017 – ORLANDO, FL
SARAH SCARPACE PETERS , PHARMD, MPH, BCOP
ASSOCIATE PROFESSOR, PHARMACY PRAC TICE
ALBANY COLLEGE OF PHARMACY AND HEALTH SC IENCES
2
Pharmacist objectives 1. Describe the mechanism of action of new therapies
2. Counsel on the side effect profile of new therapies
3. Identify the place in therapy of oral chemotherapy in cancer treatment
3
Pharmacy Technician objectives 1. Identify new oral oncology agents that have recently been FDA-
approved
2. Identify the type of cancer new oral chemotherapy agents will treat
3. Understand the importance of the gradual transition from IV chemotherapy to oral chemotherapy
4
Overview Timeline of 2017 FDA oral chemotherapy drug indications for existing drugs (5 + 2 new drugs for benign heme)
Detailed review of new drugs approved by the FDA in 2017 ◦ Acute myeloid leukemia (2)
◦ Lung cancer (1 “.5”)
◦ Ovarian cancer (2 “.5”)
◦ Breast cancer (2)
Summary
5
Old drugs, new indications FDA APPROVALS IN 2017 FOR ORAL CHEMO DRUGS ALREADY ON THE MARKET….
6
2017 New FDA indications for old drugs
7
January June December October
2/22: lenalidomide maintenance s/p transplant
3/30: osimertinib regular approval T790M met. lung 2nd line 3/31 palbociclib regular approval HR+/HER2- met. breast with AI
6/22: dabrafenib/tremetinib regular approval V600E BRAF met. Lung 1st line
8/2: ibrutinib breakthrough/orphan drug for GVHD
6/23: betrixaban for VTE prophy in hospitalized patients
7/7 L-glutamate powder for sickle cell anemia
U.S. Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. Drug approval reports by month. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed 9/22/2017.
And some new drugs for benign heme…
NEW! Oral chemo drugs FDA APPROVALS FOR NOVEL ORAL CHEMO DRUGS IN 2017
8
2017 FDA Approvals for New Drugs
9
January June December October
12/19/16 Rucaparib accelerated approval g/s-BRCA ovarian 3rd+ line
3/13 ribociclib + AI HR+/HER2- met. Breast 1st line
7/17 neratinib for HER2+ early breast s/p adjuvant trastuzumab
8/1 enasidenib for adults with IDH2mutated r/r AML
U.S. Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. Drug approval reports by month. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed 9/22/2017.
3/27 niraparib maintenance for met. Ovarian s/p CR or PR to platinum
4/27 lorlatinib breakthrough ALK/ROS1+ met. NSCLC s/p another ALK therapy 4/28 brigatinib orphan drug for ALK+ NSCLC s/p crizotinib 4/28 midostaurin ASM, SM-AHN, MCL, and FLT3+ AML with 7+3 regimen
8/17 olaparib tablet formulation
Acute Myeloid Leukemia ENASIDENIB
MIDOSTAURIN
10
FDA Indications
ENASIDENIB (IHDFA ®)
IDH2 mutation positive AML
MIDOSTAURIN (RYDAPT ®)
Aggressive systemic mastocytosis (ASM)
Systemic mastocytosis with associated hematological neoplasm (SM-AHN)
Mast cell leukemia (MCL)
FLT3+ AML with the 7+3 regimen
11
Isocitrate dehydrogenase 1 and 2
citrate
aconitrate
isocitrate Alpha -
ketoglutarate
Et cetera
12
Isocitrate dehydrogenase
Mutated isocitrate dehydrogenase
2-hydroxyglutarate
Kreb’s Cycle
Mutated isocitrate dehydrogenase
LESS
Dang L et al. Nature 2009; 462 (7274): 739-744
IDH2 mutations
occur in about 12% of all AML patients
Isocitrate dehydrogenase 1 and 2
Progenitor cells
Terminally differentiated
cells
13
Histone + CH3
histone
Isocitrate dehydrogenase
Normal IDH1/2 demethylates
progenitor cells to promote
differentiation Mutated isocitrate dehydrogenase
Mutated IDH1/2 prevents
differentiation and promotes cell proliferation
Lu C et al. Nature 2012; 482 (7390): 474-478.
NCT 01915498 Study Design
14
Phase 1/2 Primary Endpoint: safety, MTD N = 239 USA, France, UK Advanced r/r AML or MDS with RAEB IDH2 mutation positive ECOG 0 – 2
5 dose levels at BID
8 dose levels at once daily
Dose Escalation Serum 2-
hydroxyglutarate levels
Serum drug levels
Efficacy by investigator review of peripheral blood and bone marrow samples
Stein EM et al. Blood 2017; 130(6): 722-731.
Enasidenib 100 mg once daily selected for
expansion phase
Efficacy Outcomes
15
Overall Response Rate = 40.3%
Median Response duration = 5.8 months
Median Overall Survival = 9.3 months
Stein EM et al. Blood 2017; 130(6): 722-731.
Side effects – grade 3 or 4
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
Most Common Side Effects
Treatment-related adverse events
Hyperbilirubinemia Retinoic acid syndrome Anemia Thrombocytopenia Tumore Lysis Syndrome Decreased appetite
16 Stein EM et al. Blood 2017; 130(6): 722-731.
FDA Indications
ENASIDENIB (IHDFA ®)
IDH2 mutation positive AML
MIDOSTAURIN (RYDAPT ®)
Aggressive systemic mastocytosis (ASM)
Systemic mastocytosis with associated hematological neoplasm (SM-AHN)
Mast cell leukemia (MCL)
FLT3+ AML with the 7+3 regimen
17
Midostaurin Mechanism of Action Multikinase inhibitor
FLT3 –both wild type and mutant
KIT – both wild and D816V mutant
PDGFR alpha/beta
VEGFR 2
Protein kinase C family (serine/threonine PKC)
18 Rydapt [package insert]. Novartis; East Hanover, NJ; April 2017
RATIFY/CALGB 10603 Study Design
19
Phase 3 Primary Endpoint: OS N = 717 in 17 countries Newly diagnosed AML FLT3 point mutations in tyrosine kinase
domain or FLT3 internal tandem duplication mutation
Age 18 - 59 Hydroxyurea allowed 5 days pre-entry No concomitant meds that prolong QT or
QT interval >500 msec
Midostaurin 50 mg BID x 14 days days 8-21 q28days + standard 7+3 chemotherapy
Placebo on midostaurin schedule + standard 7+3 chemotherapy
Randomized
Double-Blind Bone marrow day
21 of cycle 1 of induction; if 2nd cycle of induction if needed
4 cycles of consolidation if CR after induction
If remission after consolidation, maintenance midostaurin or placebo for 12 more cycles
Transplant not required but allowed
1:1
*two 25 mg capsules
Stone RM et al. New Engl J Med 2017; 377: 454-464
Stone RM et al. N Engl J Med 2017;377:454-464
Overall Survival
Median OS = 74.7 months Midostaurin versus 25.6 months placebo
ALK mutation+ metastatic NSCLC BRIGATINIB (FDA-APPROVED)
LORLATINIB (NOT FDA-APPROVED BUT BREAKTHROUGH THERAPY DESIGNATION BY FDA)
21
FDA Indications
BRIGATINIB (ALUNBRIG ®)
ALK+ NSCLC s/p crizotinib (orphan drug)
LORLATINIB *NOT FDA APPROVED
Breakthrough status for ALK+ NSCLC s/p 1 or more ALK therapies
22
ALTA-1L Study Design
23
Phase 2 Primary Endpoint: Overall Response Rate N = 222 18 countries Locally advanced or metastatic NSCLC ALK+ Refractory to crizotinib No other ALK-directed therapies ECOG 0 – 2 No pulmonary interstitial disease No drug-related pneumonitis No unstable brain mets
Brigatinib 90 mg once daily
Brigatinib 90 mg once daily x 7 days then 180 mg daily
Randomized
Open-label
Disease assessment q8 weeks through cycle 15 (28 day cycles) then q 12 weeks until progression
Days 8 and 15 pulmonary symptom assessment
1:1
Kim DW et al. J Clin Oncol 2017; 35 (22): 2490-2498
Efficacy Outcomes OVERALL RESPONSE RATE
0%
20%
40%
60%
ORR
90 mg daily
90 mg daily x 7 days then 180 mg daily
MEDIAN PROGRESSION-FREE SURVIVAL
0
5
10
15
PFS (months)
90 mg daily
90 mg daily x 7 days then 180 mg daily
24
Investigator-assessed
Kim DW et al. J Clin Oncol 2017; 35 (22): 2490-2498
Adverse Events (Any Grade) Brigatinib 90 mg daily x 7 days then 180 mg daily
40% 38%
34%
30%
27%
23% 21%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
Any Grade
Nausea Diarrhea Cough Increased CPK2 Fatigue Vomiting Hypertension
Grade 3/4 over 2%: Increased CPK (9%); Hypertension (6%); Rash (3%); 2%: dyspnea and back pain
25 Kim DW et al. J Clin Oncol 2017; 35 (22): 2490-2498
Ovarian Cancer (metastatic) R UCA PA R I B
N I R A PA RI B
OLA PA R IB TA BLETS
26
FDA Indications
Olaparib (Lynparza ®) Rucaparib (Rubraca ®) Niraparib (Zejula ®)
• maintenance treatment • recurrent epithelial ovarian,
fallopian tube, or primary peritoneal cancer
• complete or partial response to platinum-based chemotherapy
• maintenance treatment • recurrent epithelial ovarian,
fallopian tube, or primary peritoneal cancer
• complete or partial response to platinum-based chemotherapy
deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.
deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies.
27
Lynparza [package insert]. Wilmington, DE: Astra-Zeneca; August 2017
Zejula [package insert]. Waltham, MA: Tesaro; March 2017 Rubraca [package insert]. Boulder, CO: Clovis Oncology, Inc; December 2016
Synthetic Lethality and BRCA
28 Ashworth A. A synthetic lethal therapeutic approach: poly (ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol 2008; 26(22): 3785-3790
Homologous repair mechanism are standard way normal cells repair double-strand breaks in DNA
Alternative repair mechanisms, such as non-homologous end-joining or single-strand annealing are used in the absence of BRCA1 or BRCA2
PARP-1 inhibition blocks single-strand break repair but not double-strand break repair
Synthetic Lethality
29
Gene 1 Gene 2 Outcome of Drug Therapy
No mutation No Mutation No effect
No mutation Mutation No effect
Mutation No Mutation No effect
Mutation Mutation Effect
When drug therapy works when only both genes of a pair are defective, there is a larger therapeutic window -PARP inhibitors won’t interfere with DNA repair in those cells that are heterozygous for BRCA mutations or which have normal BRCA genes (ie., the noncancerous cells)
Ashworth A. A synthetic lethal therapeutic approach: poly (ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol 2008; 26(22): 3785-3790
Clinical Trials Olaparib Rucaparib Niraparib
Name of study SOLO-2 Study 19 ARIEL2 Part 1 NOVA/ ENGOT-OV16
Phase 3 2 2 3
Randomized Yes Yes No Yes
Double-blind Yes Yes No Yes
Placebo-controlled Yes Yes No Yes
Sample size 295 265 206 553
Role of BRCA germline Irrespective Somatic, germline, or none
Germline BRCA vs. not
Disease Relapsed, platinum-sensitive
Recurrent, platinum-sensitive
Recurrent, platinum-sensitive, high-grade
Recurrent, platinum-sensitive, high grade
Prior therapies 2 prior platinums 2 prior platinums 1 or 2 platinums 2 prior platinums
Intervention 300 mg BID 400 mg BID 600 mg BID 300 mg once daily
Primary Endpoint PFS PFS PFS PFS
30 Swisher EM et al. Lancet Oncol 2017; 18: 75-87 Mirza MR et al. N Engl J Med 2016; 375 (22): 2154-2164
Pujade-Lauraine E et al. Lancet Oncol 2017; 18(9): 1274-1284.
Ledermann JA et al. Lancet Oncol 2016; 17(11): 1579-1589. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. J Clin Oncol 2015; 33 93): 244-250.
PFS (months)
31 Swisher EM et al. Lancet Oncol 2017; 18: 75-87 Mirza MR et al. N Engl J Med 2016; 375 (22): 2154-2164
Pujade-Lauraine E et al. Lancet Oncol 2017; 18(9): 1274-1284.
Ledermann JA et al. Lancet Oncol 2016; 17(11): 1579-1589.
19.1
0
7
0
12.8
5.7
21
12.9
0
5
10
15
20
25
gBRCA nonBRCA olaparib SOLO2 Olaparib Study 19 Rucaparib ARIEL2 niraparib NOVA
BRCA-mutated BRCA wild-type
Note Olaparib Study 19 did not meet threshold for statistical significance for follow-up of Overall Survival in both BRCA(set at p<0.0095; p = 0.025) and non-BRCA patients
Adverse Events – Overall
76%
66%
43% 38%
33%
15%
21%
79% 78%
36%
44%
33%
14%
46%
73.60%
59.40%
50.10%
36.20%
19.40%
61.30%
39.80%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Nausea Fatigue RBC Vomiting Diarrhea PLT Constipation
Olaparib SOLO-2 Rucaparib Niraparib
32 Swisher EM et al. Lancet Oncol 2017; 18: 75-87 Mirza MR et al. N Engl J Med 2016; 375 (22): 2154-2164
Pujade-Lauraine E et al. Lancet Oncol 2017; 18(9): 1274-1284.
Adverse Events – Grade 3 or 4
1%
19%
5%
0
4%
0
22%
12%
33.80%
25.30%
19.60%
8.20% 8.20%
0 0%
5%
10%
15%
20%
25%
30%
35%
40%
PLT RBC WBC Hypertension Fatige LFTs
Olaparib SOLO-2 Rucaparib Niraparib
33 Swisher EM et al. Lancet Oncol 2017; 18: 75-87 Mirza MR et al. N Engl J Med 2016; 375 (22): 2154-2164
Pujade-Lauraine E et al. Lancet Oncol 2017; 18(9): 1274-1284.
Breast Cancer R I BOCI CL I B N ER AT I N IB FOR H ER 2+ EA R LY STAGE BR EA ST CA N CER A FT ER A DJUVA N T T R A ST UZ UM A B
34
FDA Indications
RIBOCICLIB (KISQALI®)
HR+/HER2- advanced or metastatic breast cancer with an Aromatase inhibitor
NERATINIB(NERLYNX ®)
Extended adjuvant treatment of early stage breast cancer after trastuzumab adjuvant therapy
35 Nerlynx [package insert]. Los Angeles, CA: Puma Biotechnology, Inc; July 2017. Kysqali [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; March 2017.
ABEMACICLIB (VERZENIO®)
HR+/HER2- advanced or metastatic breast cancer with fulvestrant after endocrine therapy
HR+/HER2- advanced or metastatic breast cancer in women and men as monotherapy after endocrine therapy and chemotherapy
Verzenio [package insert]. Indianapolis, IN: Eli Lilly & Co; September 2017
cdk pathway
36
Cyclin-dependent kinases promote progression from G1 phase to S phase by phosphorylating retinoblastoma protein
Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol 2006; 24(11): 1770-1783.
G2 phase – growth, DNA
repair, preparation for division
M phase – mitosis/ cell
division
G1 phase – growth and
normal metabolic functions
S phase – DNA
replication
Retinoblastoma protein
Cyclin dependent kinase
Phosphorus
Study Designs MONALEESA 2 MONARCH 2 MONARCH 1
Phase 3 3 2
R, PC, DB Yes Yes No (open-label, single arm)
Primary Endpoint PFS PFS Objective Response Rate
Population HR+/HER2-, recurrent/metastatic
HR+/HER2-, advanced breast cancer HR+/HER2- metastatic breast cancer
Prior therapies None Neoadj. Or adjuvant endocrine therapy
Endocrine therapy and 1 or 2 chemotherapies
Notes No concomitant QT interval-prolonging meds
Protocol amended after safety review to lower dose from 200 mg BID to 150 mg BID
Intervention Ribociclib 600 mg (three 200 mg capsules) daily days 1-21 q 28 days + letrozole 2.5 mg daily
Abemaciclib 150 mg BID + fulvestrant 500 mg IM days 1, 15 cycle 1 then day 1 q 28 days
Abemaciclib 200 mg BID
37 Hortobagyi GN et al. N Engl J Med 2016; 375(18): 1738-1748.
Sledge GW et al. J Clin Oncol 2017; 35(25): 2875-2884. Dickler MN. Clin Cancer Res 2017; 23(17): 5218-5224
MONALEESA-2 PFS
Hortobagyi GN et al. N Engl J Med 2016;375:1738-1748
Median PFS not reached in ribociclib arm at time of interim analysis; median PFS in placebo arm = 14.7 months
18-months PFS rate was 63% in ribociclib arm vs. 42.2% in placebo arm
0%
10%
20%
30%
40%
50%
60%
70%
18-month PFS
Ribociclib Placebo
HR = 0.56 (95% CI, 0.43 – 0.71; p = 3.92 x 10-6)
MONARCH 2 PFS
HR = 0.553 (95% CI, 0.449 – 0.681) 16.4
9.3
0
2
4
6
8
10
12
14
16
18
median PFS (months)
abemaciclib + fulvestrant placebo + fulvestrant
Sledge GW et al. J Clin Oncol 2017; 35(25): 2875-2884.
MONARCH 1
Dickler MN. Clin Cancer Res 2017; 23(17): 5218-5224
Result
Objective Response Rate 19.7% (95% CI, 13.3 – 27.5%)
PFS (median) 6 months
OS (median) 17.7 months
Adverse Events – All Grades Selected most common
74.3
51.5 50.3 36.5 35 33.2 29.3 27.2 24.9
46 45.1 42.6 39.9
86.4
15.6 25.9
11.6 13.6
0
20
40
60
80
100
letrozole + ribociclib abemaciclib + fulvestrant
41
% O
F PA
TIEN
TS
Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 2016; 375(18): 1738-1748.
Dickler MN. Clin Cancer Res 2017; 23(17): 5218-5224
Adverse Events – Grade 3/4 Selected most common
59.3
1.2 1.2 2.4 4.2 9.3 5.7
26.5
13.4 7.2 2.7 6.6 2.3 4.1
0 10 20 30 40 50 60 70
letrozole + ribociclib abemaciclib + fulvestrant
42
% O
F PA
TIEN
TS
Febrile neutropenia = 1.5% in letrozole + ribociclib vs. none in letrozole + placebo Febrile neutropenia = 0.009% in abemaciclib + fulvestrant vs. none in fulvestrant + placebo
Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 2016; 375(18): 1738-1748.
Dickler MN. Clin Cancer Res 2017; 23(17): 5218-5224
FDA Indications
RIBOCICLIB (KISQALI®)
HR+/HER2- advanced or metastatic breast cancer with an Aromatase inhibitor
NERATINIB(NERLYNX ®)
Extended adjuvant treatment of early stage breast cancer after trastuzumab adjuvant therapy
43 Nerlynx [package insert]. Los Angeles, CA: Puma Biotechnology, Inc; July 2017. Kysqali [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; March 2017.
ABEMACICLIB (VERZENIO®)
HR+/HER2- advanced or metastatic breast cancer with fulvestrant after endocrine therapy
HR+/HER2- advanced or metastatic breast cancer in women and men as monotherapy after endocrine therapy and chemotherapy
Verzenio [package insert]. Indianapolis, IN: Eli Lilly & Co; September 2017
ExteNET Study Design
44
Phase 3 Primary Endpoint: invasive DFS N = 2840 Europe, Asia, Australia, NZ, NA, SA Early stage HER2+ breast cancer after
neoadj. and adj. trastuzumab Initially Stage 1- 3, node positive or
negative and trastuzumab completed up to 2 years prior
Later Stage 2-3, node positive only and tras within 1 year
Neratinib 240 mg once daily
Matching Placebo daily
Randomized
Double-blind
Disease assessment q8 weeks through cycle 15 (28 day cycles) then q 12 weeks until progression
Days 8 and 15 pulmonary symptom assessment
1:1
Chan A et al. Lancet Oncol 2016; 17: 367-377
Protocol was amended 5 times!
ExteNET 2-year DFS 93.90%
91.00%
0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
70.00%
80.00%
90.00%
100.00%
2-year DFS
Neratinib Placebo
45 Chan A et al. Lancet Oncol 2016; 17: 367-377
HR = 0.67; (95% CI, 0.50 – 0.91)
ExteNET Adverse Events
96%
41% 43%
2%
27%
2%
26%
3%
24%
2%
20%
1%
16%
1% 0%
20%
40%
60%
80%
100%
120%
Any Grade Grade 3/4
Diarrhea Nausea Fatigue Vomiting Abdominal Pain Headache Rash
46 Chan A et al. Lancet Oncol 2016; 17: 367-377
Practical information Dose & Schedule
Pills/dose With food?
pH -dependent absorption
Renal/ Hepatic Adjustments
CYP drug interactions
QT interval issues
Top 5 Side Effects
Enasidenib (Idhifa®) Warning: Differentiation syndrome
100 mg daily
One tablet
Doesn’t matter
no None/unknown severe renal/hepatic
1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, UGT1A1, pgp, inhibitor; 2D6 and 3A4 inducer
No Nausea; vomiting; diarrhea; elevated bili; decreased appetite
Midostaurin*
(Rydapt ®) Warning: Pulmonary toxicity
50 mg (AML) or 100 mg BID
Two or Four 25 mg capsules
Yes + antiemetic
No None 3A4 substrate Yes Nausea; vomiting; diarrhea; edema; fatigue
Brigatinib (Alunbrig®) Warnings: ILD, htn; cpk; pancreatitis; glucose; vision
90 mg daily x 7 days then 180 mg daily
One or two 90 mg capsules
Doesn’t matter
No No 3A substrate and inducer
No Nausea; diarrhea; fatigue; cough; headache 47
*for drug alone in non-AML patients
None should be used in pregnancy!
Practical information Dose & Schedule
Pills/dose With food? pH –absorb?
Renal/ Hepatic
CYP drug interactions
QT interval issues
Top 5 Side Effects
Niraparib (Zejula ®) warning: htn, HR, myelo-suppression
300 mg once daily
Three 100 mg capsules
Doesn’t matter
No No though unknown in severe renal/hepatic
None PgP substrate
None Nausea; PLT; fatigue; RBC; constipation
Rucaparib (Rubraca®)
600 mg BID
Two 200 mg capsules
Doesn’t matter
No No though unknown in severe renal/hepatic
(in vitro) 1A2, 2C9, 2C19,3A4 inhibitor; 1A2 inducer
None Nausea; fatigue; constipation; vomiting; LFTs
Olaparib (Lynparza®) Warning: pneumonitis
300 mg TABLET BID
Two 150 mg TABLETS
Doesn’t matter
No Reduce CrCl<60
3A4 substrate
None Nausea; fatigue; RBC; vomiting; diarrhea
48
All PARP inhibitors have a warning about risk of myelodysplastic syndrome
None should be used in pregnancy!
Practical information Dose & Schedule
Pills/dose With food? pH -dependent absorption
Renal/ Hepatic
CYP drug interactions
QT interval issues
Top 5 Side Effects
Ribociclib (Kisqali®) Warning: QT, bili, neutropenia
600 mg days 1-21 q 28d
Three 200 mg tablets
Doesn’t matter
No Neither 3A4 substrate Probably Neutropenia; nausea; fatigue; diarrhea; alopecia
Abemaciclib (Verzenio®) Warning: diarrhea, neutropenia, LFTs, VTE
150 mg BID with fulvestrant or 200 mg BID alone
One 150 mg or 200 mg tablets
Doesn’t matter
No Severe hepatic; not known for CrCl<30
3A4 substrate No Diarrhea; neutropenia; nausea; abdominal pain; infections
Neratinib (Nerlynx®) Warning: diarrhea, LFTs
240 mg daily x 1year with prophylactic antidiarrheal cycles 1-2
Six 40 mg tablets
Yes Yes Severe hepatic
3A4 substrate; PgP inhibitor
No Diarrhea; nausea; fatigue; abdominal pain; headache 49
None should be used in pregnancy!
Questions?
Thank you for your time and the opportunity to present!
50