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Home , Avapritinib, Binimetinib, Encorafenib, Imatinib, Lenvatinib, Pemigatinib

New Drug Update – Solid Tumor Drugs

MELANI RUDISILL, PHARMD, BCOP CLINICAL PHARMACY SPECIALIST NOVANT HEALTH FORSYTH MEDICAL CENTER Disclosures I have nothing to disclose. Objectives 1. Review pharmacology of drugs that gained FDA approval within the past year 2. Summarize literature supporting recently approved oncology drugs and new indications for immunotherapy and PARP inhibitors 3. Identify the place in therapy for newly approved oncology drugs Breast

FAM - DERUXTECAN - NXKI

NERATINIB +

TUCATINIB + TRASTUZUMAB / CAPECITABINE

SACITUZUMAB Fam--nxki

Approved date and indication • December 2019 for patients with HER2+, unresectable and/or previously treated with 2+ anti-HER2 therapies in the metastatic setting MOA • HER2 antibody conjugated with a topoisomerase I inhibitor; following binding of HER2, fam-trastuzumab is internalized and undergoes linker cleavage by lysosomal enzymes leading to DNA damage and cell death Dosing & Administration • 5.4 mg/kg IV every 3 weeks; administer 1st infusion over 90 minutes; subsequent infusions over 30 minutes

Enhertu (fam-trastuzumab deruxtecan-nxki) [package insert]. Basking Ridge, NJ: Daiichi Sankyo, Inc.; 2019. Fam-Trastuzumab Deruxtecan-nxki

Destiny-Breast01 Study design and Two part, open-label, single group study of HER2+, unresectable and/or Population metastatic breast cancer previously treated with Intervention Part 2: Trastuzumab Deruxtecan 5.4 mg/kg IV every 3 weeks 1°: ORR: 60.9% (95% CI, 53.4 to 68.0) Endpoints/ 2°: PFS: 16.4 months (95% CI 12.7 to not reached) Outcomes: n=184 2°: DOR: 14.8 months (95% CI, 13.8 to 16.9) Safety , , ,

Clinical Pearls: ORR: overall response rate PFS: progression free survival • Do not substitute fam-trastuzumab with trastuzumab or DOR: duration of response ado-trastuzumab emtansine • Monitor for interstitial lung disease and pneumonitis • Moderate emetic risk potential

Modi S, Saura C, Yamashita T, et al. N Engl J Med 2020;382:610-21.

Approved date and indication • February 2020 in combination with capecitabine in advanced/metastatic HER2+ breast cancer who have received 2+ prior anti-HER2 based regimens in the metastatic setting MOA • Pan-HER inhibitor irreversibly binding to HER1, HER2, and HER4

Dosing & Administration • Neratinib 240 mg by mouth daily with food • Following adjuvant trastuzumab therapy in the extended adjuvant, early stage • In combination with capecitabine in the metastatic or advance setting after 2+ prior anti-HER2 regimens

Nerlynx (Neratinib) [package insert]. Los Angeles, CA: Puma Biotechnology, Inc.; 2017. Neratinib + Capecitabine

NALA trial Study design and Multinational, randomized, open-label, phase III of heavily pretreated Population stage IV HER2+ metastatic breast cancer after 2+ anti-HER2 therapies Neratinib 240 mg daily + capecitabine 750 mg/m2 twice daily Comparators 1,250 mg daily + capecitabine 1000 mg/m2 twice daily 1°: PFS: 47% vs 38% (6 mo.); 29% vs 15% (12 mo.); 16% vs 7% (18 mo.) Endpoints/ 1°: OS: 21 months vs 18.7 months (p=0.2) Outcomes: n=621 2°: ORR: 32.8% vs 26.7% (p=0.1201) 2°: DOR: 8.5 months vs 5.6 months (p=0.0004) Safety GI, fatigue/asthenia, arthralgia, UTI, URTI, renal impairment

OS: overall survival Clinical Pearls: • Antidiarrheal prophylaxis recommended • Separate from antacids and H2- antagonists

Saura C, Oliveira M, Feng YH, et al. Presented at 2019 ASCO Annual Meeting. Abstract 1002.

Approved date and indication • April 2020 for patients with HER2+ advanced/metastatic breast cancer, with or without brain metastases who have received 1+ anti-HER2 based regimen (in combination with trastuzumab and capecitabine) MOA • Inhibits of HER2 and HER3 leading to disruption of MAPK and AKT signaling and cell proliferation Dosing & Administration

• Tucatinib 300 mg by mouth twice daily; with or without food

Tukysa (Tucatinib) [package insert]. Bothell, WA: Seattle Genetics Inc.; 2020. Tucatinib + Trastuzumab/Capecitabine

HER2CLIMB trial Study design and Randomized, double-blind, placebo-controlled in HER2+ locally Population advanced/metastatic, +/- brain metastases after 1+ anti-HER2 therapies Comparators Tucatinib 300 mg twice daily or placebo + trastuzumab and capecitabine 1°: PFS: 33.1% vs 12.3%; p<0.001 Endpoints/ 2°: Median OS: 21.9 months vs 17.4 months; p=0.00480 Outcomes: n=612 2°: Median PFSBrainMets: 7.6 months vs 5.4 months; p<0.00001 2°: ORR: 40.6% vs 22.8%; p=0.00008 Safety , palmar-plantar reactions, nausea/, fatigue

Clinical Pearls • Severe diarrhea and hepatotoxicity can occur • Hepatic dose adjustment: 200 mg by mouth twice daily • Drug interactions with CYP3A4, CYP2C8, and P-gp substrates

Murthy R.K., et al. N Engl J Med 2020;382:597-609. HER2 Directed Inhibitor Mechanism

EGFR

HER1 HER2 HER4 HER3

Lapatinib Tucatinib Neratinib Sacituzumab govitecan-hziy

Approved date and indication • April 2020 in patients with metastatic triple negative breast cancer after 2+ prior therapies

MOA • Trop-2 directed antibody and topoisomerase inhibitor conjugate composed of SN-38 and CL2A (linker) – causes DNA damage resulting in and cell death Dosing & Administration • Sacituzumab 10 mg/kg IV days 1 and 8 every 21 days • 1st infusion over 3 hours; subsequent infusions over 1-2 hours if tolerated • Premedicate with acetaminophen, H1 and H2 blockers for prevention of reactions as well as two or three drug regimen for nausea prevention

Trodelvy (Sacituzumab govitecan-hziy) [package insert]. Morris Plains, NJ: Immunomedics, Inc.; 2020. Sacituzumab govitecan-hziy

IMMU-132-01 Trial Study design and Phase 1/2, open-label, multicenter, single-arm trial in patients with Population metastatic triple negative breast cancer after 2+ prior treatments Intervention Sacituzumab 10 mg/kg IV days 1 and 8 every 21 days 1°: ORR: 33.3% (95% CI: 24.6 to 43.1) Endpoints/ 2°: Median DOR: 7.7 months (95% CI: 4.9 to10.8) Outcomes: n=108 2°: PFS: 5.5 months (95% CI, 4.1 to 6.3) 2°: Median OS: 13 months (95% CI, 11.2 to 13.7) Safety Nausea, diarrhea, neutropenia, fatigue, anemia

Clinical Pearls: • Severe neutropenia - consider G-CSF for secondary prophylaxis • Severe diarrhea – administer atropine (early) or loperimide (late) diarrhea • Drug interactions with UGT1A1 inducers and inhibitors

Bardia A, Mayer I.A., Vahdat L.T., et al. N Engl J Med 2019;380:741-51. How does the mechanism of neratinib differ to other HER2 directed inhibitors?

A. Neratinib irreversibly binds to HER1, HER2, and HER4 B. Neratinib reversibly binds to HER1, HER2, and HER4 C. Neratinib targets and binds to HER1 and HER2 D. Neratinib targets and binds to HER1 and HER3

A

Gynecologic Cancer

PEMBROLIZUMAB + NIRAPARIB OLAPARIB + + Lenvatinib Study 111/KEYNOTE-146 Study design and Single-arm, multicenter, open-label, multi-cohort trial metastatic Population endometrial carcinoma progressing after 1+ prior therapies in any setting Intervention Lenvatinib 20 mg by mouth daily + pembrolizumab 200 mg IV every 3 wks

1°: ORRWK24 (not MSI-H/dMMR): 38% (95% CI: 29% to 48%) 2°: Median DOR: 21.2 months (95% CI, 7.6 months to not estimable (NE)) Endpoints/ - Estimated DOR >6 months: 87% (95% CI, 72% to 95%) Outcomes: - Estimated DOR >12 months: 63% (95% CI, 45% to 77%) n=108 2°: Median PFS: 7.4 months (95% CI, 5.3 to 8.7 months) 2°: Median OS: 16.7 months (95% CI, 15.0 months to NE) Safety Fatigue, , diarrhea, , nausea

Makker V, Taylor M, Aghajanian C, et al. J Clin Oncol 2020. New Indications – PARP Inhibitors

Niraparib: QUADRA1/PRIMA2 - FDA approved October 2019 and April 2020

• October 2019: QUADRA: Single-arm, phase 2 - advanced ovarian/fallopian tube/primary peritoneal cancer treated with 3+ prior regimens whose cancer is HRD+ status • Intervention: Niraparib 300 mg by mouth once daily • ORR: 24% (95% CI: 16,34); Median DOR: 8.3 months (95%CI: 6.5, not estimable) • April 2020: PRIMA: Double-blind, placebo-controlled - first-line maintenance for advanced epithelial ovarian/fallopian tube/primary peritoneal cancer in a CR or PR to first-line platinum chemo • PFS 13.8 months vs 8.3 months (P<0.0001)

Olaparib: PAOLA-1 – FDA approved May 20203

• Randomized, double-blind, placebo-controlled study in first-line maintenance for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer in a complete or partial response to first-line platinum • Intervention: Olaparib 300 mg by mouth twice daily+ bevacizumab vs placebo + bevacizumab • Median PFS: 22.1 months vs 16.6 months (P<0.001)

1. Moore K, Slvarez Secord A, Geller M, et al. Lancet oncol 2019;20(5):636-648. 2. Gonzalez Martin A, et al. PRIMA/ENGOT-0V26/GOG-3012. 2019. 3. Ray-Coquard I, Pautier P, Pignata S, et al. N Engl J Med 2019; 381: 2416-2428. Prostate Cancer

DAROLUTAMIDE APALUTAMIDE ENZALUTAMIDE RUCAPARIB OLAPARIB Darolutamide

Approved date and indication

• July 2019 in patients with non-metastatic castration resistant prostate cancer

MOA

• Nonsteroidal androgen-receptor antagonist that competitively inhibits androgen binding, and receptor translocation and transcription to decrease cell proliferation

Dosing & Administration

• Darolutamide 600 mg by mouth twice daily with food

Nubeqa (Darolutamide) [package insert]. Whippany, NJ: HealthCare Pharmaceuticals, Inc.; 2019. Darolutamide ARAMIS Study design and Multicenter, double-blind, placebo-controlled trial in patients with non- Population metastatic castration resistant prostate cancer Darolutamide 600 mg by mouth twice daily vs matching placebo Intervention - All patients received a concurrent GnRH analog or had a previous bilateral orchiectomy Endpoints/ 1°: Median MFS: 40.4 months vs 18.4 months (p<0.0001) Outcomes: n=1,509 2°: OS: darolutamide associated with a 29% lower risk of death (P=0.45) Fatigue, pain in extremity, rash Safety - Ischemic heart disease (4.3%) and (2.1%) were more common in darolutamide arm

MFS: -free survival Clinical Pearls: • eGFR 15-29 mL/min or Child-Pugh class B: 300 mg twice daily • with P-gp and CYP3A4 inducers (decreases darolutamide exposure) – to a lesser extent than other antiandrogens

Fizazi K, Shore N, Tammela T, et al. N Engl J Med 2019;380:1235-46. New Indications – Androgen Receptor Inhibitors

Apalutamide and enzalutamide: Phase III, randomized, double-blind, placebo- controlled trial in patients with metastatic castrate sensitive prostate cancer (mCSPC) Apalutamide: TITAN - FDA approved September 20191 • Intervention: Apalutamide 240 mg by mouth daily vs matching placebo • All patients also received androgen deprivation therapy (GnRH or orchiectomy) • 1°: OS: 82% vs 74% (P=0.005) • 1°: 24 month rPFS: 68% vs 48% (P<0.001) Enzalutamide: ARCHES - FDA approved December 20192 • Intervention: Enzalutamide 160 mg by mouth daily vs matching placebo • All patients also received androgen deprivation therapy (GnRH or orchiectomy) • 1°: OS: data not mature • 1°: rPFS: NR vs 19.4 months (p<0.0001) Common adverse effects in both trials: • Fatigue, arthralgia, rash, HTN, hot rPFS: radiographic progression-free survival flash, diarrhea, fracture

1. Chi K.N., Agarwal N, Bjartell A, et al. N Engl J Med 2019;381:13-24. 2. Armstrong A, Szmulewitz R, Petrylak D, et al. J Clin Oncol 2019;37:2974-2986. Antiandrogen Comparison

Darolutamide Apalutamide Enzalutamide - NMCRPC - CRPC - NMCRPC - MCSPC - MCSPC Once daily without regard Once daily without regard Twice daily with food to food to food Trial did not show a significant increase in risk Risk of seizure, fracture, Risk of seizure, fracture, of seizures, falls, fractures, falls, HTN falls, HTN fatigue Drug interaction with Drug interactions with Fewer drug interactions CYP3A4 inducers CYP3A4 inducers All are category 1 recommended for NMCRPC in patients with PSADT <10 months New Indications – PARP Inhibitors

1 Rucaparib: TRITON2 - FDA approved May 2020 • Multi-center, single arm trial of BRCA-mutated (germline and/or somatic) mCRPC • Intervention: Rucaparib 600 mg PO twice daily • All patients also received androgen deprivation therapy (GnRH or orchiectomy) • 1°: ORR: 44% (95% CI: 31, 57)

Olaparib: PROfound - FDA approved May 20202 • Prospective, randomized, bio-marker-selected, phase 3 trial of HRR mutated germline or somatic mCRPC after enzalutamide or abiraterone • Intervention: Olaparib 300 mg PO twice daily vs either enzaluamide or abiraterone • All patients also received androgen deprivation therapy (GnRH or orchiectomy) • 1°: rPFS (Cohort A/overall population) • Cohort A: 7.4 months vs 3.6 months (P<0.0001) Common ADEs in both trials: • Overall: 5.8 months vs 3.5 months (P<0.001) • Fatigue, GI, anemia, thrombocytopenia, rash, increased ALT/AST

1. Abida W, Campbell D, Patnaik A, et al. Clin Cancer Res. 2020. 2. De Bono J, Fizazi M, Saad F, et al. N Engl J Med 2020;382:2091-2102. Darolutamide, apalutamide, and enzalutamide are all listed as category 1 recommendations per the NCCN guidelines for systemic therapy in NMCRPC when PSADT <10 months. In which patient may darolutamide be preferred over the other androgen receptor inhibitors? 1. A patient with a significant pill burden who is often forgetful of 2. A patient recently discharged from a rehab facility recovering at home from a recent fracture after falling 3. A patient on concomitant therapy due to a recent deep vein thrombosis A. 1, 2, and 3 B. 2 and 3 only C. 1 and 3 only

B

Lung Cancer

DURVALUMAB + CHEMOTHERAPY

LURBINECTEDIN

CAPMATINIB

SELPERCAPTINIB

NIVOLUMAB + +/- DOUBLET

BRIGATINIB Lurbinectedin

Approved date and indication • June 2020 in patients with metastatic SCLC who had disease progression on/after platinum-based chemotherapy MOA • Alkylating drug that binds the guanine region of DNA leading to formation of DNA double strand breaks and disruption in transcription and DNA repair pathways, subsequently leading to apoptosis Dosing & Administration

• Lurbinectedin 3.2 mg/m2 IV over 1 hour every 3 weeks

Zepzelca (Lurbinectedin) [package insert]. Palo Alto, CA: Jazz Pharmaceuticals, Inc.; 2020. Lurbinectedin PM1183-B-005-14 Study design and Single-arm, phase II, open-label, basket trial in metastatic SCLC who had Population disease progression on/after platinum-based chemotherapy Intervention Lurbinectedin 3.2 mg/m2 IV every 21 days 1°: ORR: 35% (95% CI: 26%, 45%) Endpoints/ 2°: Median DOR: 5.3 months (95% CI: 4.1,6.4) Outcomes: n=105 2°: PFS: 3.5 months (95% CI: 2.6,4.3) 2: OS: 9.3 months (95% CI: 6.3,11.8) Myelosuppression, fatigue, alterations in and function, nausea, Safety diarrhea

Clinical Pearls: • Initiate treatment only if ANC is >1500 cells/mm3 and platelet count >100,000/mm3 • Premedicate with steroids ( 8 mg or equivalent) and serotonin antagonists

Trigo J, Subbiah V, Besse B, et al. Lancet Oncol. 2020;21(5):645-654.

Approved date and indication

• May 2020 in patients with metastatic NSCLC with METex14 skipping mutation

MOA

• Tyrosine kinase inhibitor that inhibits the phosphorylation of MET and downstream signaling proteins and proliferation and survival of MET-dependent cancer cells

Dosing & Administration

• Capmatinib 400 mg by mouth twice daily with or without food

Tabrecta (Capmatinib) [package insert]. East Hanover, NJ: Pharmaceuticals Corporation; 2020. Capmatinib GEOMETRY mono-1 Study design/ Phase II multicenter: ALK(-), EGFR , stage IIIB/IV NSCLC with METex14 mutation population WT Intervention Capmatinib 400 mg PO twice daily Reported as cohort 4 (n=69)/cohort 5b (n=28) 1°: ORR: 40.6%/67.9% (95% CI 28.9 to 53.1/ 47.6 to 84.1) Endpoints/ 2°: DOR: 9.72 months/11.14 months (95% CI, 5.5 to 12.9/ 5.5 to not estimable) Outcomes 2°: Median PFS: 5.42 months/9.69 months (95% CI, 4.1 to 6.9/ 5.5 to 13.8) *Preliminary intracranial response: 54% in patients with brain metastases Safety Peripheral , pneumonitis, fatigue, N/V

Clinical Pearls: • Monitor for new/worsening pulmonary symptoms (interstitial lung disease/pneumonitis) • Drug interactions with CYP3A4 inducers

Garon EB, Heist RS, Seto T, et al. Abstract CT082. Presented at: AACR Annual Meeting; 2020.

Approved date and indication • May 2020 in patients with metastatic NSCLC with RET alterations MOA

• Tyrosine kinase inhibitor that inhibits both mutated and wild-type RET which inhibits cell proliferation of tumor cell lines that harbor this protein

Dosing & Administration

• <50 kg: 120 mg by mouth twice daily • >50 kg: 160 mg by mouth twice daily • If taking with PPI: administer with food; if taking with an H2 antagonist: separate 2 hours before or 10 hours after food

Retevmo (Selpercatinib) [package insert]. Indianapolis, IN: Lilly USA, LLC; 2020. Selpercatinib LIBRETTO-001 Study design/ Multicenter, multi-cohort: prior platinum chemo or treatment naïve population whose tumors had RET alterations Intervention Selpercatinib 160 mg PO twice daily Prior platinum doublet (95% CI) (n=105) - 1°: ORR 68% (58 to 76), CNS ORR 91% (59 to 100) - 2°: DOR: 20.3 months (13.8 to 24) Endpoints/ - 2°: PFS: 18.4 months (12.9 to 24.9) Outcomes Treatment naïve (95% CI) (n=34) - 1°: ORR: 85% (69 to 95) - 2°: Median DOR and PFS not reached Safety HTN, LFT elevations, dry mouth, diarrhea

Clinical Pearls: • Can cause QT interval prolongation – monitor patients who are at risk of developing QTc prolongation

Drilon A, Oxnard G, Wirth L, et al. Presented at the IASLC World Conference on Lung Cancer2019.

Approved date and indication • May 2020 in patients with advanced ALK+ NSCLC

MOA

• Tyrosine kinase inhibitor with activity against multiple kinase targets (ALK, ROS1, - like -1 receptor, FLT3) as well as EGFR deletions, and point mutations

Dosing & Administration

• 90 mg by mouth once daily x 7 days, then increase to 180 mg by mouth once daily • May be taken with or without food

Alunbrig (brigatinib) [package insert]. Cambridge, MA: Ariad Pharmaceuticals, Inc.; 2017. Brigatinib ALTA 1L Study design and Randomized, open-label, multicenter trial in those with advanced ALK+ Population NSCLC naïve to previous ALK therapy Brigatinib 180 mg by mouth once daily – 7 day lead in at 90 mg PO daily Comparators 250 mg by mouth twice daily 1°: Estimated PFS: 24 months vs 11 months (p<0.0001) Endpoints/ 2°: ORR: 74% vs 62% Outcomes: n=275 *Intracranial objective response: 83% vs 33% Safety GI, fatigue, rash, , headache, hypertension

Clinical Pearls: • CrCl 15-29 mL/min: Reduce dose ~50%; Child-Pugh C: Reduce dose ~40% • Monitor heart rate, CPK, blood glucose, blood pressure, /, s/sx of ILD/pneumonitis or visual disturbances • Drug interactions with CYP3A4 inhibitors and inducers

Camidge R, Him HR, Ahn M, et al. Presented at the ESMO Asia Congress 2019. Tyrosine Kinase Inhibitor MET RET HGF Selpercatinib

P P Mutated ALK ALK Capmatinib

PI3K/AKT RAS/MAPK Brigatinib PI3K/AKT/mTOR JAK/STAT

Survival, proliferation New Indications – Immunotherapy + chemotherapy: CASPIAN - FDA approved March 20201 • Randomized, multicenter, active-controlled, open-label trial as first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC) • Durvalumab 1500 mg IV every 3 weeks (with chemo) then every 4 weeks (single agent maintenance) vs chemotherapy alone (etoposide + cisplatin OR ) • 1°: OS: 13 months vs 10.3 months (p=0.0047)

Nivolumab + ipilimumab +/- platinum doublet - FDA approved May 20202,3

• CHECKMATE-227: randomized, trial in metastatic/recurrent NSCLC, no prior therapy; PD-L1 >1% • Nivolumab + ipilimumab versus platinum-doublet every 3 weeks • 1°: OS: 17.1 months vs 14.9 months (p=0.007) • CHECKMATE-9LA: randomized, phase 3 trial in metastatic or recurrent NSCLC; any PD-L1 • Nivolumab + ipilimumab + chemotherapy versus chemotherapy alone x 4 cycles • 1°: OS: 14.1 months vs 10.7 months Common ADEs in trials: • Fatigue, rash, GI,

1. Paz-Ares L, Dvorkin M, Chen Y, et al. Lancet 2019;394:1929-39. 2. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. N Engl J Med 2019;381:2020-31. 3. Reck M, Ciuleanu TE, Dols MC, et al. J Clin Oncol. 2020;38(suppl):abstr 9501. Based on the CASPIAN trial, durvalumab expanded its indications to include which of the following indications? A. Durvalumab in combination with chemotherapy is a preferred first line treatment option in patients with NSCLC B. Durvalumab is the preferred immunotherapy option in patients LS-SCLC C. Durvalumab is now an option in unresectable, stage III NSCLC without progression following chemotherapy and radiation D. Durvalumab in combination with chemotherapy is a preferred first- line treatment option in patients with ES-SCLC

D

Hepatocellular Cancer NIVOLUMAB + IPILIMUMAB + BEVACIZUMAB New Indications – Immunotherapy

Nivolumab + Ipilimumab: CHECKMATE-040 - FDA approved March 20201 • Multicenter, multiple cohort (cohort 4), open-label in HCC who progressed/were intolerant to ; n=49 • Nivolumab + ipilimumab x 4, then single-agent nivolumab every 2 weeks • 1°: ORR: 33% (95% CI: 20, 48) • Safety: Fatigue, GI, rash, musculoskeletal pain, hypothyroidism

Atezolizumab + Bevacizumab: IMbrave150 - FDA approved May 20202

• Open-label, phase 3, randomized trial in locally advanced unresectable or metastatic HCC who have not received prior systemic therapy; n=501 • Atezolizumab + bevacizumab every 3 weeks versus sorafenib 400 mg by mouth twice daily • 1°: OS: Not reached vs 13.2 months (p=0.0006) • 1°: PFS: 6.8 months vs 4.3 months (P<0.0001) • Safety: Hypertension, fatigue,

1. Yao T, Kang YK, Kim TU, et al. Presented at 2019 ASCO Annual Meeting; 2019. 2. Finn R, Qin S, Ikeda M, et al. N Engl J Med 2020;382:1894-905. Cholangiocarcinoma Pemigatinib

Approved date and indication • April 2020 in patients with previously treated, unresectable locally advanced/metastatic cholangiocarcinoma with a fibroblast (FGFR2) fusion

MOA

• Small molecule kinase inhibitor that targets FGFR 1, 2, and 3 leading to inhibition of phosphorylation and signaling decreasing the proliferation and survival of malignant cells

Dosing & Administration

• 13.5 mg by mouth once daily – 14 days on, 7 days off (21 day treatment cycle)

Pemazyre (pemigatinib) [package insert]. Wilmington, DE: Incyte Corporation; 2020. Pemigatinib FIGHT-202 Study design and Multicenter, open-label single-arm trial in previously treated, unresectable Population locally advanced/metastatic cholangiocarcinoma with a FGFR2 fusion Intervention Pemigatinib 13.5 mg by mouth once daily x 14 days on then 7 days off Endpoints/ 1°: ORR: 36% (95%CI: 27% to 45%) Outcomes: n= 107 2°: Median DOR: 7.5 months Safety Hyperphosphatemia, alopecia, GI, fatigue, dysgeusia, dry eye/mouth

Clinical Pearls: • Monitor for hyperphosphatemia • Monitor for eye/vision changes: ophthalmologic exam prior to initiation, every 2 months x 6, every 3 months thereafter • CYP3A4 drug interactions

Abou-Alfa GK, Sahai V, Hollebecque A, et al. Lancet Oncol. 2020 May;21(5):671-684. Urothelial/Bladder Cancer -EJFV PEMBROLIZUMAB Enfortumab vedotin-ejfv

Approved date and indication • December 2019 in patients with locally advanced or metastatic urothelial cancer after prior immunotherapy and chemotherapy MOA

• Nectin-4 directed antibody-drug conjugate with activity due to release of MMAE via proteolytic cleavage inducing cell cycle arrest and apoptotic cell death by disrupting the microtubule network within the cell

Dosing & Administration

• 1.25 mg/kg (max 125 mg) IV infusion over 30 minutes on days 1, 8, 15 of 28 day cycle

Padcev (enfortumab vedotin-ejfv) [package insert]. Northbrook, IL: Astellas Pharma US, Inc.; 2019. Enfortumab vedotin-ejfv EV-201 Study design and Phase II, single-arm, multicenter trial in locally advanced or metastatic Population urothelial cancer after prior immunotherapy and chemotherapy Intervention Enfortumab vedotin-ejfv 1.25 mg/kg on days 1, 8, 15 of 28 day cycle Endpoints/ 1°: ORR: 44% (95% CI: 35.1 to 53.2) Outcomes: n= 125 2°: DOR: 7.6 months (95% CI: 6.3 to not estimable) Safety Fatigue, peripheral neuropathy, rash, alopecia, GI, dysgeusia, dry eye/skin

Clinical Pearls: • Closely monitor blood glucose: DKA has occurred regardless of pre-existing • Monitor for peripheral neuropathy, skin reactions, and s/sx of ocular disorders

Rosenberg J, O’Donnell P, Valar A, et al. J Clin Oncol 37:2592-2600. New Indication – Immunotherapy

FDA approval: BCG-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for cystectomy

Pembrolizumab: KEYNOTE-057 – FDA approved January 2020

• Multicenter, phase 2, single-arm trial of patients with BCG-unresponsive, high-risk, NMIBC with CIS with or without papillary disease who were unwilling or unfit to undergo radical cystectomy • Pembrolizumab 200 mg IV every 3 weeks up to 24 months • 1°: Complete response: 41% (95% CI: 31, 51) • 2°: Median DOR: 16.2 months (0.0+, 30.4+) Common ADEs in trial: • Fatigue, rash, GI, arthralgia, hypothyroidism

Balar A, Kulkarni G, Uchio E, et al. J Clin Oncol. 2019, no.7 (suppl): 350. + PEMBROLIZUMAB Encorafenib + Cetuximab BEACON CRC – FDA approved April 2020 Study design and Phase 3, Randomized, open-label trial in BRAF V600E mutation-positive Population metastatic CRC with progression after 1+ prior lines Encorafenib 300 mg by mouth daily + cetuximab Comparators Encorafenib 300 mg + + cetuximab FOLFIRI + cetuximab OR irinotecan + cetuximab *Reported for doublet therapy vs control* Endpoints/ 2°: OS: 8.4 months vs 5.4 months (p=0.0003) Outcomes: n= 441 2°: PFS: 4.2 months vs 1.5 months (p<0.0001) 2°: DOR: 6.1 months vs not reached Safety Fatigue, GI, acneiform, arthralgia, rash

Kopetz S, Grothey, A, Yaeger R, et al. N Engl J Med. 2019;381:1632-43. New Indication – Immunotherapy FDA approved for first-line treatment of patients with unresectable or metastatic MSI-H or mismatch repair deficient (dMMR) colorectal cancer

Pembrolizumab: KEYNOTE-177 – FDA approved June 2020

• Randomized, open-label, phase 3 trial in untreated unresectable or metastatic MSI-H or dMMR colorectal cancer • Pembrolizumab vs investigator’s choice (mFOLFOX/FOLFIRI +/- bevacizumab or cetuximab) • 1°: PFS: 16.5 months vs 8.2 months (p=0.0002) • HR = 0.60 (40% reduction in the risk of disease progression) • 1°: OS: Not mature • Interim results presented – study is ongoing Common ADEs in pembrolizumab arm: • Fatigue, musculoskeletal pain, GI, rash, dyspnea • Grade 3-5: 22% vs 66%

Andre T, Shiu K-K, TW Kim, et al. ASCO20 Virtual Scientific Program. Abstract LBA4. Pancreatic Cancer OLAPARIB New Indication – PARP Inhibitor

Olaparib: POLO – FDA approved December 2019

• Double-blind, placebo-controlled trial in gBRCAm metastatic pancreatic adenocarcinoma • Maintenance olaparib 300 mg by mouth twice daily versus matching placebo • Maintenance was started 4-8 weeks after last dose of first-line chemotherapy

Common ADEs in trial: • GI, anemia, neutropenia, , URTI, arthralgia, headache

Golan T, Hammel P, Reni M, et al. N Engl J Med 2019;381:317-27. GIST Avapritinib

Approved date and indication • January 2020 in patients with unresectable or metastatic GIST harboring a PDGFR exon 18 mutation, including D842V mutations MOA

• Tyrosine kinase inhibitor that interferes with tumor cell proliferation by targeting the autophosphorylation of KIT D816V and PDGFRA D842V, mutants associated with resistance to approved kinase inhibitors

Dosing & Administration

• 300 mg by mouth once daily on an empty

Ayvakit (avapritinib) [package insert]. Cambridge, MA: Blueprint Medicines Corporation.; 2020. Avapritinib NAVIGATOR Study design and Multi-center, single-arm, open-label trial in unresectable or metastatic Population GIST harboring a PDGFR exon 18 mutation, including D842V mutations Avapritinib 400 mg by mouth once daily (initial) reduced to recommended Intervention dose of 300 mg by mouth once daily due to toxicity 1°: ORR: 84% in PDGFR exon 18 mutation (95% CI: 69% to 93%); 89% in Endpoints/ PDGFR D842V mutations (95% CI: 75% to 97%) Outcomes: n= 43 2°: DOR: Not reached Safety Edema, fatigue/asthenia, cognitive impairment GI, hair color changes, rash

Clinical Pearls: • Reduce initial dose to 100 mg daily when used with a moderate CYP3A4 inhibitor; avoid strong inhibitors • Dose adjustments recommended for CNS toxicity

Heinrich M, von Mehren M, Jones RL, et al. Blueprint Medicines Corporation. Published August 7, 2019. Ripretinib

Approved date and indication • May 2020 in GIST patients previously treated with 3+ kinase inhibitors including

MOA

• Tyrosine kinase inhibitor that inhibits KIT and PDGFRA kinase, including wild type, primary and secondary mutations.

Dosing & Administration

• 150 mg by mouth once daily with or without food

Qinlock (ripretinib) [package insert]. Waltham, MA: Deciphera Pharmaceuticals, LLC; 2020. Ripretinib INVICTUS Study design and Randomized, phase 3, double-blind, placebo-controlled trial in GIST Population previously treated with 3+ kinase inhibitors including imatinib Comparators Ripretinib 150 mg by mouth once daily versus matching placebo 1°: PFS: 6.3 months vs 1.0 months (p<0.0001) Endpoints/ 2°: ORR: 9% vs 0% (not statistically significant) Outcomes: 2°: OS: 15.1 months vs 6.6 months – not evaluated for statistical significance Alopecia, fatigue, GI, myalgia, hand foot syndrome Safety *new primary cutaneous , HTN, and cardiac dysfunction

Clinical Pearls: • Monitor blood pressure and ejection fraction prior to initiation and as needed; monitor for any skin reactions • Dose adjustments recommended for arthralgia/myalgia, HTN, hand-foot syndrome

Van Mehren M, Attia S, Bauer S, et al. INVICTUS: 2019. Sarcoma TAZEMETOSTAT Tazemetostat

Approved date and indication • January 2020 in patients with metastatic/locally advanced

MOA

• Inhibitor of EZH1 and EZH2 which leads to transcriptional repression

Dosing & Administration

• 800 mg by mouth twice daily with or without food

Tazverik (tazemetostat) [package insert]. Cambridge, MA: Epizyme, Inc.; 2020. Tazemetostat EZH-202 Study design and Single-arm cohort (cohort 5) of a multicenter trial in patients with Population metastatic/locally advanced epithelioid sarcoma Intervention Tazemetostat 800 mg by mouth twice daily Endpoints/ 1°: ORR: 15% (95% CI, 7% to 26%) Outcomes: n= 62 1°: DOR: 67% of those responding had responses >6 months Safety GI, fatigue, pain

Clinical Pearls: • Avoid concomitant use of strong and moderate CYP3A4 inhibitors and inducers • Warning listed for risk of developing secondary malignancies, (T-cell lymphoblastic , MDS, and AML) New Drug Update – Solid Tumor Drugs

MELANI RUDISILL, PHARMD, BCOP CLINICAL PHARMACY SPECIALIST NOVANT HEALTH FORSYTH MEDICAL CENTER