Faculty Information Laura Bobolts, PharmD, BCOP Danielle Roman, - - PowerPoint PPT Presentation

Faculty Information

Laura Bobolts, PharmD, BCOP Senior Vice President, Clinical Strategy and Growth Oncology Analytics, Inc Plantation, Florida Andrea Iannucci, PharmD, BCOP Assistant Chief Pharmacist, Oncology and Investigational Drugs Services PGY2 Oncology Pharmacy Residency Program Director, UC Davis Health Clinical Professor, UC Davis School of Medicine UCSF School of Pharmacy Sacramento, California Danielle Roman, PharmD, BCOP Manager, Clinical Pharmacy Services Allegheny Health Network Pittsburgh, Pennsylvania

Educational Objectives

After completion of this activity, participants will be able to:

• Explain the pathophysiology, prognosis, and challenges of treating

metastatic triple-negative breast cancer (TNBC)

• Analyze the clinical and safety evidence to support current and emerging

therapies and treatment algorithms for TNBC

• Explore the economic impact of TNBC and identify strategies to optimize

medication therapy for patients with TNBC

Metastatic Triple-Negative Breast Cancer

Danielle Roman, PharmD, BCOP Manager, Clinical Pharmacy Services Allegheny Health Network Pittsburgh, Pennsylvania

Triple-Negative Breast Cancer (TNBC)

• Lack of expression of ER, PR, and

absence of HER2 overexpression

• Most fatal subtype of breast cancer
• Generally displays a short time to

relapse

• 5-year OS for metastatic TNBC = 11%

Sharma P. The Oncologist. 2016;21:1050-1062; Triple-negative breast

• cancer. American Cancer Society (ACS). Accessed November 3, 2020.

cancer.org/cancer/breast-cancer/understanding-a-breast-cancer- diagnosis/types-of-breast-cancer/triple-negative.html Breast cancer facts and figures, 2019-2020. ACS. Published 2019. Accessed August 14, 2020. cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts- and-figures/breast-cancer-facts-and-figures-2019-2020.pdf

TNBC

ER, estrogen receptor; PR, progesterone receptor; OS, overall survival

Clinical Features of TNBC

• Aggressive natural history
• Worse prognosis compared with hormone receptor (HR)-positive breast cancer
• High 5-year recurrence rate for early-stage disease, which peaks 2-3 years after diagnosis
• High propensity for brain and lung metastases
• Median OS for metastatic TNBC is 12-18 months
• More commonly seen in the following women:
• Younger
• Obese
• Premenopausal
• African American

Lebert JM, et al. Curr Oncol 2018;25:S142-150; Azim HA, et al. Breast J. 2020;26:69-80.

Pathologic and Molecular Features of TNBC

• High pathologic grade
• Molecular heterogeneity
• Strong correlation with BRCA1/2 mutation status
• 15%-20% of patients with TNBC demonstrate a germline BRCA mutation
• Somatic p53 mutations are common but not clinically actionable
• Tumor-infiltrating lymphocyte (TIL) infiltration is more common than other subtypes
• Basal-like subtype is the most common intrinsic subtype by gene expression analysis
• P13K activation is common

Sharma P. The Oncologist. 2016;21:1050-1062; Azim HA, et al. Breast J. 2020;26:69-80; Lebert JM, et al. Curr Oncol. 2018;25:S142-150.

Biomarker Testing in Metastatic TNBC

Breast cancer subtype Biomarker Detection FDA-approved agents Any BRCA1/2 mutation Germline sequencing Olaparib Talazoparib Any NTRK fusion FISH, NGS, PCR (tissue block) Larotrectinib Entrectinib Any MSI-H/dMMR IHC, PCR (tissue block) Pembrolizumab Any TMB-H NGS Pembrolizumab Triple negative PD-L1 expression (considered positive if ≥1% on tumor-infiltrating immune cells) IHC Atezolizumab + albumin- bound paclitaxel

BRCA, breast cancer gene; dMMR, deficient mismatch repair; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; MSI-H, microsatellite instability-high; NGS, next-generation sequencing; NTRK, neurotrophic tropomyosin receptor kinase; PCR, polymerase chain reaction; TMB-H, tumor mutational burden-high.

National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Breast Cancer, v6.2020;

• Keytruda. Prescribing information. Merck & Co, Inc; October 2020.

Treatment Options for Metastatic Breast Cancer

NCCN Clinical Practice Guidelines in Oncology. Breast Cancer, v6.2020.

Hormonal therapies HER2-targeted agents Chemotherapy PARP inhibitors (for germline BRCA1/2 mutation) Immunotherapy (for PD-L1+)

Treatment Options for Metastatic TNBC

NCCN Clinical Practice Guidelines in Oncology. Breast Cancer, v6.2020.

Hormonal Therapies HER2-targeted agents Chemotherapy PARP inhibitors (for germline BRCA1/2 mutation) Immunotherapy (for PD-L1+)

Factors Influencing Treatment Decision

Lebert JM, et al. Curr Oncol. 2018;25:S142-S150.

Rate of disease progression Performance status Tumor burden Previous treatment Patient preferences

Treatment Algorithm

NCCN Clinical Practice Guidelines in Oncology. Breast Cancer, v6.2020.

Metastatic TNBC

PD-L1 positive Germline BRCA1/2 mutation

PD-L1 negative; no germline BRCA1/2 mutation

Atezolizumab + nab- paclitaxel Olaparib Talazoparib NTRK fusion Larotrectinib Entrectinib MSI-H; dMMR Pembrolizumab Chemotherapy

Chemotherapy Options: Preferred Regimens

First or Subsequent Lines

NCCN Clinical Practice Guidelines in Oncology. Breast Cancer, v6.2020.

Anthracyclines Taxanes

• Doxorubicin
• Liposomal doxorubicin
• Paclitaxel

Antimetabolites

• Capecitabine
• Gemcitabine

Platinum (for germline BRCA1/2 mutation)

• Carboplatin
• Cisplatin

Chemotherapy + immunotherapy (PD-L1+)

• Atezolizumab + albumin-bound paclitaxel

Microtubule inhibitors

• Vinorelbine
• Eribulin

Use of Taxanes in mTNBC

Agent Every 3 weeks Weekly Adverse effects (AEs) Docetaxel 60-100 mg/m2 IV 35 mg/m2 IV 6 weeks on/2 weeks off

• Edema (↓ with steroid

prophylaxis), myelosuppression (neutropenia); GI AEs—stomatitis, N/V/D

• Should not be used with liver

dysfunction Paclitaxel 175 mg/m2 IV 80 mg/m2 IV

• Neuropathy and myalgias, infusion-

related reactions

• May be used with mild-moderate

liver dysfunction Albumin bound/ nab-paclitaxel 260 mg/m2 IV 100-125 mg/m2 IV 3 weeks on/1 week off

• Shorter infusion time/less risk of

reactions; does not require steroid premedication

Mauri D, et al. Cancer Treat Rev. 2010;36(1):69-74.

GI, gastrointestinal; IV, intravenous; N/V/D, nausea/vomiting/diarrhea.

TNT Trial: Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2+ Breast Cancer

Median PFS Carboplatin Docetaxel P value All patients 3.1 months 4.4 months 0.4 BRCA1/2 patients 6.8 months 4.4 months 0.002

Tutt A, et al. Nat Med. 2018;(24)5:628-637.

• Significantly improved response to carboplatin in BRCA1/2 patients
• ORR 68% vs 33%
• PFS favored carboplatin in the BRCA1/2 group
• No OS benefit found; carboplatin = 12.8 months and

docetaxel = 12 months

• More grade 3/4 AEs in the docetaxel group

Conclusion: Data from this trial confirm that carboplatin is active in BRCA1/2-mutated advanced breast cancer. Carboplatin is a viable option for treatment of patients with breast cancer with BRCA1/2 mutation.

ORR, objective response rate; PFS, progression-free survival.

EMBRACE: Eribulin

• Primary end point: OS improved with eribulin vs TPC (13.1 mo vs 10.6 mo; HR, 0.81; P = 0.041)
• FDA approved for patients with metastatic breast cancer who have received ≥2 prior therapies for

metastatic disease (including anthracycline and taxane)

Cortes J, et al. Lancet. 2011;377:914-923.

Study design: phase 3,

• pen-label

N = 762

• Locally recurrent or

metastatic disease

• 2-5 previous

chemotherapy regimen

R A N D O M I Z E D

2:1 n = 508 Eribulin 1.4 mg/m2 IV Days 1, 8 every 21 days n = 254 Treatment of physician’s choice (TPC) Included 19% patients with TNBC.

Other Chemotherapy Options

First or Subsequent Lines

NCCN Clinical Practice Guidelines in Oncology. Breast Cancer, v6.2020.

• Cyclophosphamide
• Docetaxel
• Albumin-bound paclitaxel
• Epirubicin
• Ixabepilone
• Sacituzumab govitecan-hziy*
• AC (doxorubicin/cyclophosphamide)
• EC (epirubicin/cyclophosphamide)
• CMF (cyclophosphamide/methotrexate/fluorouracil)
• Docetaxel/capecitabine
• GT (gemcitabine/paclitaxel)
• Gemcitabine/carboplatin
• Paclitaxel/bevacizumab
• Carboplatin + paclitaxel or albumin-bound paclitaxel

Recommended regimens: Useful in certain circumstances:

*Recommended for patients who have received ≥2 prior therapies for metastatic disease.

ASCENT: Sacituzumab Govetecan-hziy

• ORR (primary end point) = 33.3% (3 complete response; 33 partial response)
• Median DOR = 7.7 months
• Clinical benefit rate = 45.4%
• PFS = 5.5 months
• OS = 13 months

Study design: open- label, basket design, phase 1/2 N = 108 patients

• mTNBC
• Received ≥2 previous

anticancer therapies for metastatic disease Sacituzumab govetecan-hziy 10 mg/kg IV days 1, 8 every 21 days

Bardia A, et al. N Eng J Med. 2019;380:741-751.

FDA approved for treatment of patients with metastatic TNBC who have received ≥2 prior therapies for metastatic disease.

DOR, duration of response.

Key Points: Role of Chemotherapy

• Generally chemotherapy-sensitive
• Single-agent versus combination chemotherapy
• Patients who require rapid response may benefit from combination therapy

despite added toxicity

• Continue until disease progression or unacceptable toxicity
• Most patients will receive multiple lines of systemic therapy as palliation

Azim HA, et al. Breast J. 2020;26:69-80; NCCN Clinical Practice Guidelines in Oncology. Breast Cancer, v6.2020.

PARP Inhibitor Monotherapy in BRCA Mutation

Phase 3 trials OlympiAD (N = 302) EMBRACA (N = 431)

Arms Olaparib vs TPC Talazoparib vs TPC TNBC population 50% 45% PFS (ITT) 7.0 vs 4.2 mo (HR, 0.58; P <0.001) 8.6 vs 5.6 mo (HR, 0.54; P <0.001) PFS (TN patients) HR, 0.43 HR, 0.60 OS 19.3 vs 17.1 mo (HR, 0.90; P = 0.513) 22.3 vs 19.5 mo (HR, 0.76; P = 0.105) ORR 59.9% vs 28.8% 62.6% vs 27.2% (P <0.001)

Robson M, et al. N Engl J Med. 2017;377:523-533; Robson M, et al. Ann Oncol. 2019;30:558-566; Litton JK, et al. N Engl J Med. 2018;379:753-763.

ITT, intent to treat; QOL, quality of life.

Significant improvement in QOL with PARP inhibitor compared with chemotherapy.

Key Points: Role of PARP Inhibitors

• Option for patients with metastatic breast cancer and germline BRCA1/2

mutation

• Approved as monotherapy
• Agents:
• Olaparib 300 mg PO twice daily
• Talazoparib 1 mg PO daily

NCCN Clinical Practice Guidelines in Oncology. Breast Cancer, v6.2020.

Immunotherapy for TNBC

• Characteristics that make TNBC more likely to respond to

immunotherapy compared with other breast cancer subtypes

• More TILs
• Higher levels of PD-L1 expression on tumor and immune cells
• Nonsynonymous mutations → activate neoantigen-specific T cells

Keenan TE, Tolaney SM. J Natl Compr Canc Netw. 2020;18:479-489.

Single-Agent Immunotherapy in mTNBC

Phase 2 Trials With Pembrolizumab

Trial

KEYNOTE-086 – Cohort A KEYNOTE-086 – Cohort B

N 170 84 PD-L1+ 61.8% 100% Prior lines ≥1 ORR (total) 5.3% NA ORR (PD-L1+) 5.7% 21.4% PFS 2 mo 2.1 mo OS 9 mo 18 mo

Adams S, et al. Ann Oncol. 2019;30:387-401; Adams S, et al. Ann Oncol. 2019;30:405-411.

KEYNOTE-119

Single-Agent Pembrolizumab vs Chemotherapy

Population CPS ≥10 CPS ≥1 Total

Pembro Chemo Pembro Chemo Pembro Chemo

OS (mo)

12.7 11.6 10.7 10.2 9.9 10.8

HR

0.78; P = 0.0574 0.86; 0.0728 0.97

PFS (mo)

2.1 3.4 2.1 3.1 2.1 3.3

HR

1.14 1.35 1.60

ORR (%)

17.7 9.2 12.3 9.4 9.6 10.6

DOR (mo) (range)

NR (2.2-32.5+) 7.1 (3.8-25.9+) 12.2 (2.2-32.5+) 6.5 (2.1-33.0+) 12.2 (2.2-32.5+) 8.3 (2.1-33.0+)

Cortes J, et al. Ann Oncol. 2019;30(suppl 5):405-411.

Trend toward greater benefit for patients with increased levels of tumor PD-L1 expression.

IMpassion130: Atezolizumab + Nab-paclitaxel in Advanced TNBC

Study design: randomized, double-blind phase 3 Eligibility:

• Metastatic or unresectable locally

advanced TNBC

• No previous chemo or targeted therapy

for metastatic disease

• Tumor specimen could be centrally

evaluated for PD-L1 expression

• ECOG PS 0-1

N = 902

R A N D O M I Z E D

1:1

n = 451 Atezolizumab 840 mg IV days 1, 15 Nab-paclitaxel 100 mg/m2 IV days 1, 8, 15 Every 28 days until disease progression n = 451 Placebo IV days 1, 15 Nab-paclitaxel 100 mg/m2 IV days 1, 8, 15 Every 28 days until disease progression

Schmid P, et al. N Engl J Med. 2018;379:2108-2121.

ECOG PS, Eastern Cooperative Oncology Group performance status.

Results

Primary end points Atezolizumab group Placebo group Statistical analysis PFS – months ITT population 7.2 5.5 HR, 0.80; 95% CI, 0.69-0.92; P = 0.002 PD-L1+ subgroup 7.5 5 HR, 0.62; 95% CI, 0.49-0.78; P <0.001 Interim OS – months ITT population 21 18.7 HR, 0.86; 95% CI, 0.72-1.02; P = 0.078 PD-L1+ subgroup 25 18 HR, 0.71 (95% CI, 0.54-0.93)

*Formal statistical analysis not conducted. PFS was 5.6 months for both the atezolizumab group and placebo group in subgroup analysis of the PD-L1- population.

Schmid P, et al. N Engl J Med. 2018;379:2108-2121; Schmid P, et al. Lancet Oncol. 2020;21:44-59.

KEYNOTE-355

Pembrolizumab + Chemotherapy

• Median PFS significantly improved with the combination of pembrolizumab + chemotherapy for

patients with CPS ≥10 (9.7 vs 5.6 mo; P = 0.0012)

• No significant difference for patients with CPS ≥1
• Well tolerated with no new safety concerns

Cortes J, et al. J Clin Oncol 2020;38(suppl 15): Abstr 1000.

Study design: randomized, double-blind phase 3 Eligibility:

• Previously untreated, locally

recurrent, inoperable, or metastatic TNBC

• ≥6 months disease-free

interval

R A N D O M I Z E D

2:1

N = 566 Pembrolizumab + chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin N = 281 Placebo + chemotherapy (same options as above)

CPS, combined positive score.

Key Points: Role of Immunotherapy for mTNBC

• No role for single-agent immunotherapy
• Exception for patients with MSI-H/dMMR or TMB-H → pembrolizumab
• FDA-approved atezolizumab + albumin-bound paclitaxel for first-line

treatment of PD-L1+ mTNBC

• No benefit in the PD-L1– subgroup
• Combination of atezolizumab + paclitaxel is not recommended
• Pembrolizumab + chemotherapy may be an option for first-line

treatment of PD-L1+ (CPS ≥10) mTNBC

Keenan TE, Tolaney SM. J Natl Compr Canc Netw. 2020;18:479-489; Keytruda. Prescribing information. Merck & Co, Inc; October 2020; FDA issues alert about efficacy and potential safety concerns with atezolizumab in combination with paclitaxel for treatment of breast cancer. US FDA. Updated September 8, 2020. Accessed October 12,

• 2020. www.fda.gov/drugs/resources-information-approved-drugs/fda-issues-alert-about-efficacy-and-potential-safety-concerns-atezolizumab-combination-paclitaxel

Role of the Androgen Receptor

• Androgen receptor (AR)-positive subtype has luminal molecular features
• ≈15% of patients with TNBC
• Typically occur at an older age and are rarely associated with germline BRCA

mutations

• Predominantly spread to lymph nodes, soft tissues, and bones
• Less chemotherapy-responsive compared with other subgroups of TNBC
• Consider treatment with:
• Enzalutamide 160 mg PO daily
• Bicalutamide 150 mg PO daily

Sharma P. The Oncologist. 2016;21:1050-1062; Azim HA, et al. Breast J. 2020;26:69-80.

Future Directions

• Novel combinations and targets
• PARP inhibitors + immunotherapy (ETCTN and DORA trials)
• AKT inhibitor + chemotherapy + immunotherapy (IPATunity130 and BEGONIA trials)
• MEK inhibitor + immunotherapy (InCITe trial)
• Novel immunotherapy agents
• Bempegaldesleukin (IL-2 pathway agonist)
• Breast cancer vaccines (PVX-410 vaccine, folate receptor α vaccine, and neoantigen vaccines)
• CAR-T
• TIL transfer
• Optimal biomarker(s) of immunotherapy response

Keenan TE, Tolaney SM. J Natl Compr Canc Netw. 2020;18:479-489.

Panel Discussion

• Have you seen incorporation of immunotherapy for eligible patients in

the first-line setting? Do you anticipate an expanded role for immunotherapy in metastatic TNBC?

• What factors do you consider when deciding between various cytotoxic

chemotherapy options for metastatic TNBC?

A Focus on the Clinical and Economic Impact to Health Systems

Andrea Iannucci, PharmD, BCOP Assistant Chief Pharmacist, Oncology and Investigational Drugs Services PGY2 Oncology Pharmacy Residency Program Director, UC Davis Health Clinical Professor, UC Davis School of Medicine UCSF School of Pharmacy Sacramento, California

Outcomes and Costs of Treatment for mTNBC

Abdalla A, et al. Future Oncol. 2019;15(9):1007-1020.

Retrospective analysis

• f outcomes for

patients with mTNBC

• OS
• Treatment
• Economic burden

Patients identified from the SEER-Medicare database

• Consolidated data from

state/regional SEER registries and Medicare enrollment and claims files from CMS

• Age ≥66 years at time of

diagnosis

• Diagnosed between

2004-2011

Healthcare resource utilization (HCRU) and costs

• Direct medical costs
• Cumulative mean costs

per-patient per-month (PPPM)

• Based on phase of

treatment or treatment pattern

• Types of healthcare

encounters/level of care

Results

Figure republished from Abdalla A, et al. Future Oncol. 2019;15(9):1007-1020, under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License.

• Median age: 76

years

• Untreated patients

were older, had worse PS, and more comorbidities

1R = 1st regimen, which is the same as first line.

Results

Group Median OS Cumulative cost per patient Mean monthly cost per patient All patients 7 months $73,586 $10,084 No systemic treatment 3.5 months $51,070 $12,101 1 treatment regimen 7.1 months $68,899 $9721 2 treatment regimens 16 months $107,214 $6853 ≥3 treatment regimens 25.3 months $143,150 $5986

Adapted from Abdalla A, et al. Future Oncol. 2019;15(9):1007-1020.

Total Costs by Phase of Treatment

Abdalla A, et al. Future Oncol. 2019;15(9):1007-1020.

Hospitalizations were more prevalent in the ≥3rd regimen arm (66.2% patients).

$0 $10,000 $20,000 $30,000 $40,000 $50,000 $60,000 Pretreatment 1st Regimen 2nd Regimen ≥ 3rd Regimen

Figure republished from Abdalla A, et al. Future Oncol. 2019;15(9):1007-1020, under the Attribution-NonCommercial- NoDerivatives 4.0 Unported License.

Survival by Number of Treatment Regimens

Apples and Oranges: Comparison of Data

Group Survival (months) Estimated monthly cost SEER data all patients 7 $10,084 SEER data 1 treatment 7.1 $9721 SEER data 2 treatments 16 $6853 SEER data ≥3 treatments 25.3 $5986 KEYNOTE-086 (2nd line) 9 $14,045 KEYNOTE-086 (1st line) 18 $14,045 Atezolizumab +NabPac (1st line) 21 (25 PD-L1+) $18,660 Olaparib 19.3 $24,673 Talazoparib 19.3 $15,309 Sacituzumab govitecan-hziy 13 $11,630

Estimated drug costs based on WAC pricing 1.8 m2 BSA or weight = 70 kg.

Abdalla A, et al. Future Oncol. 2019;15(9):1007-1020; Adams S, et al. Ann Oncol. 2019;30(3):397-404; Adams S, et al. Ann Oncol. 2019;30(3):405-411; Schmid P, et al. J Clin Oncol. 2019;37(suppl 15):1003; Robson ME, et al. Ann Oncol. 2019;30(4):558-566; Litton, et al. AACR 2020 Virtual Meeting Session VCTPL07; Bardia A, et al. N Engl J Med. 2019;380(8):741-751.

Determining Value of Treatment

• Value: measure of outcomes

achieved per level of cost

• Outcomes: PFS, OS, treatment

toxicities, QOL, capacity to work

• Direct costs: drug cost,

facility/treatment costs

• Indirect costs: loss of productivity

due to illness/toxicity; other out-of- pocket expenses

• How is value of cancer treatment

determined?

• Clinical benefit vs potential

toxicities

• Impact of treatment on QOL
• Societal benefit: cost-effectiveness

Lemieux J, Audet S. Curr Oncol. 2018;25(S1):S161-S170.

Tools to Assess Value of Cancer Treatment

• NCCN Evidence BlocksTM
• American Society of Clinical Oncology (ASCO) Value Framework:
• Comparative studies only
• Adjuvant or advanced disease
• European Society of Medical Oncology (ESMO) Magnitude of

Clinical Benefit Scale (MCBS)

• Variety of forms based on curative potential of treatment
• Includes a tool for single-arm studies (PFS or ORR outcomes)

Lemieux J, Audet S. Curr Oncol. 2018;25(S1):S161-S170; NCCN Clinical Practice Guidelines in Oncology. Breast Cancer, v6.2020; NCCN Evidence Blocks™ User Guide. Accessed September 10, 2020. www.nccn.org/evidenceblocks/pdf/EvidenceBlocksUserGuide.pdf

NCCN Clinical Practice Guidelines in Oncology. Breast Cancer, v6.2020; NCCN Evidence Blocks™ User Guide. Accessed September 10, 2020. www.nccn.org/evidenceblocks/pdf/EvidenceBlocksUserGuide.pdf

NCCN Evidence Blocks™ for mTNBC Treatment

• Rated on a scale of 1-5 from panel members
• Efficacy of regimen/agent
• Safety of regimen/agent
• Quality of evidence
• Consistency of evidence
• Affordability of regimen/agent

5 4 3 2 1 E S Q C A Example: atezolizumab/albumin-bound paclitaxel

Ranking Therapeutic Options in mTNBC

Caparica R, et al. ESMO Open. 2019;4(suppl 2):4e000504; NCCN Clinical Practice Guidelines in Oncology. Breast Cancer, v6.2020.

• 1. Clinical

trial

• No clear winner for standard, front-line therapy
• Numerous trials with novel therapies and/or combinations
• 132 active, recruiting interventional trials
• 16 phase 3 studies
• 2. Chemo-

therapy

• Single-agent:
• Taxane, anthracycline
• Less toxicity
• 3. PD-L1+
• Atezolizumab + nab-paclitaxel (if no clinical trial available)
• Data supporting benefit in front-line setting
• Not clear what benefit would be for second-line or later settings

BRCAm

• PARP inhibitor
• Platinum agent
• Consider combination therapy

in some situations:

• Good performance status
• Bulky, aggressive, symptomatic disease
• Second-line:
• Antimetabolite
• Eribulin, vinorelbine, ixabepilone
• Platinum agent

Health-System Resources for Management of Patients With mTNBC

• Care coordination
• RN case manager
• Navigator
• Transitions of care (inpatient/outpatient)
• Placement of treatment and laboratory
• rders
• Treatment authorization
• Financial coordinator/navigator
• Assess patient share of costs
• Provide options for assistance
• Social work
• Assess social support needs/resources
• Assess level of distress
• Provide support/resources
• Oncology pharmacist
• Assess appropriateness/safety of regimen
• Optimize supportive medications
• Oversight for oral medications

✓ Ensure acquisition of medications ✓ Patient adherence

• Patient education
• Oncology/infusion nurse
• Assess venous access needs
• Double-check appropriateness/safety of

treatment regimen

• Patient education
• Dietitian
• Physical therapy/occupational therapy

Optimizing Therapy for TNBC

• Comprehensive treatment plans
• Computerized provider order entry (CPOE)

preferred

• Include process for verification of accuracy

and validation of regimen

• Standardized processes: labs/assessments
• Supportive medications and interventions
• Pre-meds
• During infusion treatment
• Post infusion
• Take-home
• Dosing and administration of

medications

• Monitoring and follow-up
• Site of care
• Ambulatory administration of

medications

• 340b/PHS pricing
• Lower overhead costs vs inpatient
• Treatment authorization
• Prior to initiation of treatment
• After treatment plan has been

submitted

• Entire course/cycle of treatment
• Cancer-directed therapy
• Supportive medications

Schwieterman P, et al. Am J Health Syst Pharm. 2015;72(24).

Optimizing Oncology Drug Utilization in mTNBC

Formulary considerations

Limit “off-label” use

When therapeutically equivalent options exist, select the lowest-cost agent Develop treatment plans with preferred, evidence-based regimens

Evaluate use of biosimilars, when available

Cancer-directed therapies Supportive medications

Optimize treatment setting

Outpatient infusion Self-injection/ administration (eg, oral meds, growth factors) Home infusion?

Payer perspective

Adherence to evidence-based treatment guidelines

Ensure process for additional authorization is in place for medications added to an active treatment plan

Develop workflows to facilitate use of payer-preferred medications (eg, biosimilars)

A Focus on the Clinical and Economic Impact to Payers

Laura Bobolts, PharmD, BCOP Senior Vice President, Clinical Strategy and Growth Oncology Analytics, Inc Plantation, Florida

Managed Care Pharmacists: Focus on TNBC

Efficacy

Toxicity

Cost

• Recognize strategies to support the most

efficacious and cost-effective care

• Assess biomarkers and mutations: PD-L1, BRCA1/2,

+/- next-generation sequencing

• Support clinical trial enrollment
• Optimize medication therapy
• Ensure off-label use is supported by NCCN or literature
• Develop preferred regimens
• Leverage oncology clinical pathways
• Counsel patients and manage toxicities
• Ensure optimal supportive care medications

Cost Barriers to Newer Therapies in TNBC

Cost reduction strategies:

• Dose rounding 10%
• Develop biosimilar

G-CSF strategy

• Ensure appropriate

antiemetics planned

• Support clinical trial

enrollment

Prices are ASP +6% or AWP.

• Lynparza. Lexicomp. Updated July 23, 2020. Accessed October 15, 2020. online.lexi.com; Talzenna. Lexicomp. Updated June 22, 2020. Accessed October 15, 2020.
• nline.lexi.com; Trodelvy. Lexicomp. Updated July 29, 20. Accessed October 15, 2020. online.lexi.com; July 2020 ASP pricing file. Centers for Medicare & Medicaid

Services (CMS). Accessed October 16, 2020. cms.gov/apps/ama/license.asp?file=https%3A//www.cms.gov/files/ zip/july- 2020-asp-pricing-file.zip; Schmid P, et al. N Engl J Med. 2018;379(22):2108-2121; Robson ME, et al. Ann Oncol. 2019;30(4):558-566; Litton JK, et al. N Engl J Med. 2018;379(8):753-763; Bardia A, et al. N Engl J Med. 2019;380(8):741-751.

Regimen

• Est. drug cost

(6 mo) Duration of therapy [study] Barriers increasing cost of care Atezolizumab, nab-paclitaxel $133,237 24.1 wk (atezo); 22.1 wk (nab-paclitaxel) [IMpassion130]

• Cannot substitute paclitaxel
• FDA supported any line of

therapy despite lack of evidence beyond 1st line Olaparib $104,034 8.2 mo [OlympiAD]

• Same price 100 mg and

150 mg tabs Talazoparib $110,226 6.1 mo [EMBRACA]

• Some may need blood

transfusion support Sacituzumab govitecan $144,900 5.1 mo [IMMU-132-01]

• 180-mg single-dose vials; 4 vials

used, unless >72 kg may need >5 vials G-CSF, granulocyte colony stimulating factor.

Managed Care Tips to Ensure Appropriate Use

• Trodelvy. Prescribing information. Immunomedics, Inc; April 2020; Tecentriq. Prescribing information. Genentech Inc; July 2020; Lynparza. Prescribing information.

AstraZeneca Pharmaceuticals, LP; May 2020; Talzenna. Prescribing information. Pfizer Labs; March 2020.

• Efficacy data 1st-line mTNBC only; consider alternative therapy beyond 1st-line
• Patient MUST be PD-L1+ via IC ≥1% (SP142 Assay)
• Nab-paclitaxel may be stopped after ≈6 cycles and single-agent atezolizumab continued if no progression
• Patient MUST be germline BRCA1/2+; single-agent therapy (BID tablets for olaparib; daily caps for talazoparib)
• May switch agents for toxicity w/o progression
• Evaluate imaging: not supported to continue or use alternative PARP inhibitor upon disease progression
• Patient MUST be 3rd-line or later mTNBC; no TROP2 testing required

Atezolizumab, nab-paclitaxel PARP inhibitor (olaparib or talazoparib) Sacituzumab govitecan

Cost-Effective Analysis: Atezolizumab, Nab-Paclitaxel

Weng, et al performed a cost-effective analysis of 1st-line atezolizumab plus nab-paclitaxel (AnP) vs nab-paclitaxel in advanced TNBC

LY, life-year; QALY, quality-adjusted life-year.

Weng X, et al. Am J Clin Oncol. 2020;43(5):340-348.

Tip: Cost-effective analyses can aid in healthcare decision making to improve the efficient use of limited healthcare resources.

Result:

• Addition of atezolizumab to nab-paclitaxel is not cost-effective
• $229,360/QALY in PD-L1+ patients
• Addition of atezolizumab adds $179,359 to cost
• Atezolizumab price would need to be reduced by 48.5% to be cost-effective
• Mean outcomes were better for AnP in PD-L1+ patients
• 2.2 LYs and 1.66 QALYs (AnP) vs 1.144 LYs and 0.88 QALYs (nab-paclitaxel)

NCCN Concordance in TNBC

• Many payers follow NCCN Guidelines and compendium to verify high-quality care
• 2020 ASCO study evaluated 16,858 patients with TNBC from the California Cancer

Registry treated from 2004-2016 for NCCN concordance

• Majority of treatment did not follow NCCN Guidelines, which led to an increase in

mortality

Ubbaonu C, et al. J Clin Oncol. 2020;38(suppl 15): Abstract 1080. 0% 10% 20% 30% 40% 50% 60% 70% 80% Concordance Non-Concordance

67.5% (n = 11,386)

Concordance 82% NCCN non-concordance resulted in an increased disease-specific mortality.

Overall population

20%

Medicare members

29%

32.5% (n = 5472)

Medicaid members

Lowest and lower-middle socioeconomic status less likely to receive NCCN- adherent care. 21% 29%

Oncology Clinical Pathways in TNBC

• Detailed, evidence-based treatment protocol

paths for specific disease types and stages

• Can steer towards preferred regimens
• Reduces use of unsupported therapy to limit

risk of unwarranted toxicity

• Must be biomarker-driven and evolve based on

prior treatments

• Needs to evaluate entire treatment picture,

medical and pharmacy benefits

• Bonus: presenting clinical trial options in TNBC

Daly B, et al. J Oncol Pract. 2018;14(3):e194-e200.

Payer- marketed pathways Provider- marketed pathways Institution- based pathways

• Oncology Analytics
• New Century Health
• AIM Specialty Health
• ClinicalPath

(formerly Via Oncology)

• Value Pathways

powered by NCCN

• Dana-Farber

Clinical Pathways

• Moffitt Clinical

Pathways

TNBC Therapy Toxicities

Chemotherapy

• Myelosuppression
• Assess risk of febrile

neutropenia, ANC, and patient-specific factors

• Nausea/vomiting
• Optimize antiemetics
• Drug specific dose

limiting toxicity

PD-1/PD-L1 inhibitors

• Immune-related

adverse events (irAEs)

• Optimize supportive

care, especially when in combination with chemo

PARP inhibitors

• Myelosuppression
• Nausea/vomiting
• Prophylactic

antiemetics needed with olaparib; usually PRN for talazoparib

Sacituzumab govitecan

• Black Box Warning:
• Severe neutropenia
• Diarrhea
• Optimize premeds

and antiemetics

• Lynparza. Prescribing information. AstraZeneca Pharmaceuticals, LP; May 2020; Talzenna. Prescribing information. Pfizer Labs; March 2020; Trodelvy. Prescribing
• information. Immunomedics, Inc; April 2020.

Tips to reduce the cost of care: Proactively ensure appropriate supportive care medications are planned, reinforce counseling on adverse effects and regular monitoring, and effectively manage toxicities to reduce the risk of nonadherence.

Atezolizumab/Nab-Paclitaxel irAEs (All Grades) in TNBC per IMpassion 130 Trial

34.1% 17.3% 15.3% 4.4% 3.1% 1.1% 0.9% 0.4% 0.2% 0.2%

0% 5% 10% 15% 20% 25% 30% 35% 40% Schmid P, et al. N Engl J Med.2018;379(22):2108-2121; Tecentriq. Prescribing information. Genentech; July 2020.

• Atezolizumab toxicity: irAEs, fatigue, infusion reaction
• Nab-paclitaxel toxicity: neuropathy, neutropenia, anemia
• Monitor: labs (CBC w/ diff, CMP, TSH, free T4, serum cortisol),

peripheral neuropathy, imaging, bowel habits, dermatologic exam, O2 sats, ± PFTs, ± EKG

• Refer to label, guidelines (ASCO, NCCN) for irAE management
• Reinforce counseling as early detection of irAEs is key!

NAUSEA/VOMITING:

• Moderately emetogenic
• Premed with 5HT3,

dexamethasone ± (NK1 or olanzapine)

Sacituzumab Govitecan Toxicity

AML, acute myeloid leukemia; MDS, myelodysplastic syndrome.

• Lynparza. Prescribing information. AstraZeneca Pharmaceuticals, LP; May 2020; Talzenna. Prescribing information. Pfizer Labs; March 2020.

Monitor: CBC w/ diff (severe neutropenia), CMP, Mag/Phos, bowel habits for diarrhea (contains SN-38: active metabolite irinotecan), nausea/vomiting, infusion reaction

DIARRHEA:

• Hold drug if grade 3/4 diarrhea

(↑ ≥7 stools/day over baseline)

• May need loperamide 4 mg PO, then 2

mg w/ every diarrhea, max 16 mg/day

• May premedicate w/ atropine

INFUSION REACTIONS:

• Premedicate with H1 antag

(diphenhydramine), H2 antag (famotidine), APAP NEUTROPENIA:

• G-CSF prophylaxis not

usually needed (low risk)

• Must monitor CBC w/ diff;

Hold if ANC <1500

RARE MDS/AML:

• Risk 0.3% to <1.5%
• Evaluate CBC w/ diff for blasts
• r prolonged neutropenia

ANEMIA, NEUTROPENIA, THROMBOCYTOPENIA:

• Monitor CBC with diff, ±

ferritin and iron sat

• Transfusions as needed

DRUG-DRUG INTERACTIONS:

• Olaparib: avoid strong/mod CYP3A

inhibitors; if cannot avoid, may need to dose ↓; avoid strong/mod CYP3A inducers

• Talazoparib: P-gp inhibitors: may need to ↓

dose; BCRP inhibitors: monitor ↑ toxicity NAUSEA/VOMITING/DIARRHEA:

• Olaparib: mod-high emetogenic;

premedicate with 5HT3

• Talazoparib: minimal-low

emetogenic; PRN antiemetics

• Assess bowel habits

PARPi (Olaparib or Talazoparib) Toxicity

Monitor: Adherence!!! CBC w/ diff (baseline, monthly thereafter or PRN), renal function (dose reduced for renal impairment), monitor rare (<1%) pneumonitis with olaparib

AML, acute myeloid leukemia; MDS, myelodysplastic syndrome.

• Lynparza. Prescribing information. AstraZeneca Pharmaceuticals, LP; May 2020; Talzenna. Prescribing information. Pfizer Labs; March 2020.

Panel Discussion

Patient case: You’re an oncology pharmacist in clinic preparing to counsel JP, a 43-year-old woman with newly diagnosed metastatic TNBC that is PD-L1+ (CPS ≥10) and BRCA1/2-. The

• ncologist wants to start JP on a new therapy she recently heard of at the ASCO annual

meeting, pembrolizumab plus paclitaxel. In researching the new regimen, you discover:

• KEYNOTE-355 found the addition of pembrolizumab to chemo (paclitaxel, nab-paclitaxel, or

carboplatin/gemcitabine) reduced the risk of disease progression or death by 35%

• Pembrolizumab plus paclitaxel is neither FDA indicated at this time nor NCCN supported,

but it does have a PDUFA date of November 28, 2020

• KEYNOTE-355 is only published in meeting abstract form

Panel Discussion

• Off-label pembrolizumab plus paclitaxel in the first-line treatment of PD-L1+

(CPS ≥10), metastatic TNBC according to the KEYNOTE-355 clinical trial

• How would you handle this off-label request?
• Does the therapy meet medical necessity standards?
• Are there alternative treatment options?
• When would you start discussing this regimen

for potential formulary addition?

Conclusions

• Advances in the treatment of TNBC are quickly evolving
• Combination approaches that include the use of immune checkpoint inhibitors or
• ral targeted therapies are increasing
• It is important to continually evaluate evidence as it matures after the first release of

data in abstract form are presented

• The high cost of therapies will drive health systems and payers to look for methods

to evaluate resource utilization to optimize patient care

• Managed care pharmacists are vital to ensure access to the most efficacious and

cost-effective TNBC care

Additional Resources

• National Comprehensive Cancer Network Breast Cancer Guidelines
• www.nccn.org/professionals/physician_gls/pdf/breast.pdf
• Abdalla A, et al. Overall survival, costs and healthcare resource use by

number of regimens received in elderly patients with newly diagnosed metastatic triple-negative breast cancer. Future Oncol. 2019;15(9):1007- 1020.

• Ubbaonu C, et al. Disparities in the receipt of National Comprehensive

Cancer Network (NCCN) guideline adherent care in triple-negative breast cancer (TNBC) by race/ethnicity, socioeconomic status, and insurance

• type. J Clin Oncol. 2020;38(suppl 15): Abstract 1080.