Updates in Breast and Lung Cancers: New Pharmacotherapies€¦ · Updates in Breast and Lung...

Updates in Breast and Lung Cancers:

New Pharmacotherapies

Donald Moore, PharmD, BCPS, BCOP, DPLA

Pharmacist Clinical Coordinator – Adult Hematology/Oncology

Levine Cancer Institute

Rock Hill, SC

March 12, 2018

Disclosures

• I have no financial conflicts of interest to disclose

• I may discuss off-label use of drugs

Objectives

• Describe the role of neratinib in the extended adjuvant treatment of HER2-positive breast cancer and recommend appropriate supportive care with its use

• Examine the role of CDK4/6 inhibitors in the treatment of hormone receptor-positive metastatic breast cancer

• Analyze the clinical benefit of durvalumab consolidation following chemoradiation in non-small cell lung cancer

• Evaluate the role of alectinib and brigatinib for the treatment of ALK-positive non-small cell lung cancer

Definitions

Adverse Event Grading

• Grade 1: mild ADR, no medical intervention necessary

• Grade 2: moderate ADR, minimal/local/noninvasive intervention required

• Grade 3: severe ADR, hospitalization or invasive intervention required

• Grade 4: life-threatening, need for intensive care or emergency medical services

• Grade 5: fatal ADR

Tumor Staging

• Stage I – single, primary tumor

• Stage II – single/larger tumor,

possible lymph node

involvement

• Stage III – locally

advanced/larger tumor,

positive lymph nodes

• Stage IV – metastatic disease

Recent Approval Landscape in

Breast and Lung Cancer • 2016 and 2017 there have been a number of FDA approvals in breast and

lung cancer

• Breast – 7 FDA updates • New Drugs: 3 - neratinib, ribociclib, abemaciclib

• New Biosimilar: 1 - trastuzumab-dkst

• New Indications: 1

• Update to regular approval: 2

• Lung – 11 FDA updates • New Drugs: 1 – brigatinib (durvalumab currently under priority review)

• New Indications: 4

• Update to regular approval: 4

• Biomarker approved: 1

• Updated prescribing information: 1

Breast Cancer

• Most common cancer in women in the US (around 29%)

• Second leading cause of cancer-related death in women • 2nd only to lung cancer

• Steadily declining death rates since 1990s • Likely secondary to improved treatments in curative (adjuvant/neoadjuvant)

setting for early stage (I-III)

• Heterogenous disease with molecular subtypes • Luminal A: hormone receptor(+)/HER2(-) – 71% - favorable prognosis

• Luminal B: hormone receptor(+)/HER2(+) – 12% - poorer survival than luminal A

• HER2-enriched: hormone receptor(-)/HER2(+) – 5% - tend to be more aggressive

• Triple-negative: hormone receptor(-)/HER2(-) – 12% - poor prognosis

American Cancer Society. Breast Cancer Facts & Figures 2017-2018.

Siegel et al. CA Cancer J Clin. 2015; 65(1):5-29.

Treatment of Early Stage Breast

Cancer • Multimodal approach to management

• Surgery, radiation, pharmacotherapies

• Pharmacotherapies include cytotoxic chemotherapy, HER2-directed biologic therapies, and endocrine therapy • Selection based on risk of recurrence, comorbidities, receptor status,

stage

• Systemic adjuvant or neoadjuvant therapy for patients with early stage breast cancer with goal to CURE • Adjuvant: prevent recurrence, eradicate micrometastatic disease

• Neoadjuvant: Decrease size of tumor to minimize surgery, delivery of drugs to intact vasculature, prognostic value of determining response to chemotherapy in vivo

Invasive Breast Cancer NCCN Guidelines V 3.2017.

Stage I-III (Neo)adjuvant

Treatment

Early Stage Breast Cancer

HR positive

HER2 +/-

HR negative

HER2 positive

HR negative

HER2 negative

Endocrine therapy +/-

chemotherapy +/-

HER2-directed therapy

HER2-directed

therapy plus

Chemotherapy

Chemotherapy


Early Stage HER2-positive Breast

Cancer • Human Epidermal Growth Factor Receptor-2: oncogene, tumors tend to

be more aggressive than those that are HER2-negative

• About 20% of patients with breast cancer have HER2-positive tumors

• Was associated with a worse prognosis before the introduction of anti-HER2 therapy • Trastuzumab: anti-HER2 monoclonal antibody, binds to extracellular domain IV

of HER2 receptor

• Pertuzumab: anti-HER2 monoclonal antibody, binds to extracellular domain II of HER2 receptor

• Trastuzumab is administered concurrently with chemotherapy initially, and then continues for a total of one year of adjuvant therapy

• Addition of trastuzumab to standard chemotherapy significantly improves overall survival in women with early-stage HER2-positive breast cancer



Romond EH, et al. N Engl J Med. 2005; 353:1673-84.

Improving Adjuvant Therapy?

• Despite adjuvant trastuzumab, 23-26% of patients will have breast cancer events after a median follow-up of 5.2-8.4

• HERA: trial that assessed 24 months of treatment with trastuzumab • Longer duration of Herceptin did not improve the primary study

endpoint of disease-free survival after 8 years of follow-up

• ALTTO: Adjuvant lapatinib sequential or concurrent with trastuzumab did not improve DFS

• BETH: addition of bevacizumab to adjuvant trastuzumab x1 year did not improve 3-year disease-free survival and increased rate of grade 3/4 toxicities

Refae S et al. Curr Opin Oncol. 2016; 28:469-75.

Von Minckwitz G et al. N Engl J Med. 2017; 377:122-31.

APHINITY: Adjuvant pertuzumab

• Had been approved as neoadjuvant therapy with trastuzumab/docetaxel

• APHINITY: addition of pertuzumab to adjuvant trastuzumab x1 year

• After median follow-up of 45.4 months, the proportion of IDFS events in the ITT population was 7.1% (n=171) in the pertuzumab arm and 8.7% (n=210) for those receiving placebo (HR 0.82; 95% CI: 0.67, 1.00; p=0.047)

• High-risk patients: HR negative and node positive • HR negative - IDFS was 8.2% (n=71) and 10.6% (n=91) in the pertuzumab and

placebo arms, respectively (HR 0.76, 95% CI 0.56, 1.04)

• Node positive - IDFS was 9.2% (n=139) and 12.1% (n=181) in the pertuzumab and placebo arms, respectively (HR 0.77, 95% CI 0.62, 0.96)

• Led to pertuzumab receiving regular approval for adjuvant treatment for patients with high risk of recurrence

von Minckwitz, et al. N Engl J Med. 2017; 377:122-31.

Neratinib

• Oral, irreversible, tyrosine kinase inhibitor of HER1, HER2, and HER4

• Hypothesis that small-molecule pan-HER2 tyrosine kinase inhibition could improve outcomes with extended adjuvant therapy • Inhibition of HER2 downstream phosphorylation by neratinib may be effective

despite development of trastuzumab resistance

• Previously demonstrated efficacy in HER2 positive metastatic breast cancer • Phase II trial in trastuzumab naïve and experienced patients

• Trastuzumab naïve: ORR=56%, 16-week PFS=78%, median PFS=39.6 weeks

• Prior trastuzumab: ORR=24%, 16-week PFS=59%, median PFS=22.3 weeks

• Common ADRs: diarrhea, N/V, fatigue

• Recently has been evaluated in the adjuvant setting in the ExteNET trial

Burstein HJ et al. J Clin Oncol. 2010; 28:1301-7.

ExteNET: Adjuvant neratinib

Neratinib 240 mg

daily x12 months

Stratification

• HR status

• Nodal

status

1:1 Randomization

N=2840

n=1420

n=1420

• Stage I-III HER2-positive

breast cancer*

• Completed adjuvant

trastuzumab up to 2 years

before randomization

*Amended: stage II-III

patients had completed

trastuzumab up to 1

year previously .

Placebo

(Neo)adjuvant

chemotherapy plus

trastuzumab +/-

adjuvant endocrine

therapy

Multicenter, randomized, double-blind, phase III trial

Martin M et al. Lancet Oncol. 2017; 18:1688-700.

ExteNET continued

• Patients receiving neratinib had

significantly fewer invasive DFS

events (116 vs. 163 events; HR

0.73, 95% CI 0.57-0.92, p=0.0083)

• 5-year invasive DFS rate 90.2% vs.

87.7%

• Subgroup analysis, neratinib

favored:

• HR positive

• Trastuzumab within 1 year

• Overall survival analysis will be

available in the future

• ADRs: mostly GI

• Diarrhea, N/V, abdominal pain

Martin M et al. Lancet Oncol. 2017; 18:1688-700.

Assessment Questions #1

A patient in your clinic is completing her adjuvant trastuzumab year-

long therapy and now has considerations to initiate neratinib for a

year. Which of the following supportive care modalities are you going

to recommend?

A. Loperamide PRN diarrhea

B. Prophylactic loperamide to prevent diarrhea

C. Prophylactic diphenoxlate/atropine to prevent diarrhea

D. Octreotide to prevent diarrhea

Neratinib safety - Diarrhea

• Most common adverse event with

neratinib was diarrhea

• Grade 1-2 – 55% vs. 34%

placebo

• Grade 3 – 40% vs. 2% placebo

• Led to dose reductions in 26% of

patients

• Cause of drug discontinuation in

17%

• Occurs most frequently during first

28 days

• Loperamide prophylaxis can reduce

grade 3 incidence to <17%

NCI CTCAE – Diarrhea Severity Grading

Grade 1 Mild; <4 stools/day over baseline

Grade 2 Moderate; 4-6 stools/day over baseline

Grade 3 Severe; ≥7 stools/day over baseline;

hospitalization required

Grade 4 Life-threatening

Diarrhea prophylaxis with loperamide

Time on neratinib Dose Frequency

Days 1-14 4 mg Three times daily

Days 15-56 4 mg Twice daily

Days 57-365 4 mg PRN (Max 16 mg/day)

*Maintain 1-2 bowel movements/day

Chan A, et al. Lancet Oncol. 2016;17:367-77.

Neratinib Pearls

• FDA approved for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy

• NCCN recommendations to be considered in patients with perceived high-risk of recurrence (such as stage II-III)

• Efficacy of neratinib unknown following adjuvant pertuzumab

• Dosing: 240 mg (6 tablets) orally once daily with food for one year

• Monitoring:

• LFTs: Monthly for first 3 months, then q 3 months while on therapy

• Drug interactions:

• Avoid concomitant use with PPIs and H2RAs

• Separate neratinib dosing by 3 hours after antacids

• Avoid concomitant use with strong CYP3A4 inhibitors/inducers

Nerlynx (neratinib) [prescribing information]


Metastatic Breast Cancer

Remains an incurable disease • Goal of therapy: palliative, prolongation of survival, maximize quality of life

3-6% of patients will have MBC at breast cancer diagnosis

About 20% of patients with stage I-III will develop MBC

Median survival about 3 years

Bone and soft-tissue metastases tend to have better prognosis and are more likely to respond to endocrine therapies

HR positive breast cancers tend to be more indolent

Additional goal in HR positive breast cancer: increase time to chemotherapy


Barnett CM. Pharmacotherapy: a pathophysiologic approach; 2014.

Metastatic Breast Cancer

Treatment Metastatic Breast Cancer (MBC)

HR negative

Symptomatic visceral disease

Hormone refractory

Endocrine therapy +/- HER2 directed therapy

HR positive

Asymptomatic visceral disease

HER2 +/-

HER2 directed therapy +

chemotherapy

HER2 negative HER2 positive


Chemotherapy

Therapies for HR(+) MBC

• Premenopausal and HER-2 negative • SERM (tamoxifen)

• Ovarian ablation/suppression plus ET as for postmenopausal

• Postmenopausal and HER-2 negative • Non-steroidal AI (anastrozole, letrozole)

• Steroidal AI (exemestane)

• Fulvestrant +/- everolimus

• Tamoxifen +/- everolimus

• Exemestane + everolimus

• Megestrol acetate

• Fluoxymesterone

• Ethinyl estradiol

• Palbociclib + aromatase inhibitor

• Palbociclib + fulvestrant

• Ribociclib + aromatase inhibitor

• Abemaciclib +/- fulvestrant

• Premenopausal and HER2-positive • Tamoxifen +/- trastuzumab

• Ovarian ablation/suppression plus therapy as for postmenopausal

• Postmenopausal and HER2-positive • AI + trastuzumab

• AI+/- lapatinib

• AI +/- lapatinib + trastuzumab

• Fulvestrant +/- trastuzumab

• Tamoxifen +/- trastuzumab

• Visceral metastasis • Chemotherapy


New Drug Class: the CDK4/6

Inhibitors

• Indicated for the treatment of HR-positive, HER2-

negative metastatic breast cancer, often in combination

with anti-hormonal therapy

• Palbociclib – February 2015

• Ribociclib – March 2017

• Abemaciclib – September 2017

Cyclin-Dependent

Kinases 4 and 6 • CDK4/6 – regulates the cell-cycle

progression from G1 to S phase, protects against abnormal replication • CDK4/6-Cyclin D interaction leads to

hyperphosphorylation of retinoblastoma (Rb), then release E2F transcription factor to allow progression to S phase

• Dysregulation occurs in cancer • Occurs through loss of function of Rb

• Amplification of cyclin D1 and CDK

• HR-positive cell lines sensitive to growth inhibition by CDK4/6 inhibition

• Inhibits cellular proliferation

• Synergistic with anti-hormonal therapy

Dickson MA. Clin Cancer Res. 2014; 20:3379-83.

Palbociclib

Ribociclib

Abemaciclib

Approval Overview

Indication Dosing

Palbociclib

Initial therapy of ABC for postmenopausal women with HR(+),

HER2(-) disease in combination with an aromatase inhibitor

Disease progression following endocrine therapy for HR(+), HER2(-)

ABC in combination with fulvestrant

125 mg daily x21 days/7

days off

Ribociclib Initial therapy of ABC for postmenopausal women with HR(+),


600 mg daily x21 days/7

days off

Abemaciclib

Monotherapy for treatment of HR(+), HER2(-) ABC following

disease progression on endocrine therapy

Disease progression following endocrine therapy for HR(+), HER2(-)

ABC in combination with fulvestrant

Initial therapy of ABC for postmenopausal women with HR(+),


Monotherapy - 200 mg

po BID continuously

Combination – 150 mg

po BID continuously

PALOMA-2: Palbociclib

Palbociclib 125 mg

daily x21 days on/7

days off + Letrozole

Stratification

• Visceral vs. non-visceral

• Disease-free interval

from end of adjuvant

therapy

• Prior hormonal therapy

n=444

n=444

• Treatment-naïve advanced

breast cancer

• HR(+), HER2(-)

• Postmenopausal

• Exclusion: advanced

symptomatic visceral spread

Placebo + Letrozole

2:1 Randomization

N=666

Finn RS et al. N Engl J Med 2016; 375:1925-36.

Multicenter, randomized, double-blind, placebo-controlled phase III trial

PALOMA-2: Palbociclib

• Median PFS – palbociclib 24.8

vs. placebo 14.5 months (HR

0.58; 95% CI 0.46-0.72,

p<0.001)

• OS – data not yet mature

• Adverse events: palbociclib vs.

placebo

• Neutropenia 79.5% vs. 6.3%

• Thrombocytopenia: 15.5% vs.

1.4%

• Nausea 35.1% vs. 26.1%

• Fatigue: 37.4% vs. 27.5%

• Alopecia: 32.9% vs. 15.8%

Finn RS et al. N Engl J Med 2016; 375:1925-36.

Palbociclib Clinical Pearls

• Take with food

• Adherence, calendars, d/w patient AI is continuous

• Avoid strong CYP 3A4 inhibitors/inducers • Palbociclib dose reduction may be

needed if unable to avoid

• May need to dose reduce NTI drugs that are CYP3A4 substrates

• PPI can decrease palbociclib levels when palbociclib taken without food

• Neutropenia: Monitor CBC at baseline, beginning of each cycle, Day 14 of first 2 cycles, and then as clinically needed • Median time to onset: 15 days (13-

117 days)

• Median duration of grade 3+ neutropenia: 7 days

ANC Dose modification

Grade 1/2

(>1000/mm3)

No dose adj. required

Grade 3

(<1000)

Day 1: hold, recheck CBC in

1 week, resume when

ANC>1000

Day 15: continue, check

CBC day 22, if ANC

<500/mm3 then dose adjust

Grade 3 + fever

or grade 4

(<500/mm3)

Hold until ANC >1000,

resume at lower dose

ANC=absolute neutrophil count

Ibrance (palbociclib) [prescribing information].

MONALEESA-2 trial: Ribociclib

Ribociclib 600 mg 21

days on/7 days off plus

letrozole 2.5 mg daily 1:1 Randomization

N=668

n=334

n=334

• Treatment-naïve advanced breast cancer

• HR(+), HER2(-)

• Postmenopausal

• Previous neo/adjuvant NSAI not allowed

unless DFI > 12 months

• Exclusion: Inflammatory cancer, brain

mets, cardiac disease including increased

QTc, concomitant QT prolonging

medications, impaired GI function

Placebo plus letrozole

2.5 mg daily

Stratification

• Liver/lung

metastasis

Multicenter, randomized, double-blind, placebo-controlled phase III trial

Hortobagyi GN et al. N Engl J Med 2016; 375:1738-48.

MONALEESA-2 continued

• Median PFS not reach with

ribociclib group

• 18-month PFS: Ribociclib 63% vs.

placebo 42.2%

• PFS survival benefit seen across all

prespecified subgroups, including

visceral metastasis

• Adverse events: ribociclib vs.

placebo

• Neutropenia 74.3% vs. 5.2%

• Nausea 51.5% vs. 28.5%

• Diarrhea: 35% vs. 22.1%

• Increased ALT: 9.3% vs. 1.2%

• Increased AST: 5.7% vs. 1.2%


Ribociclib Clinical Pearls

• Taken with or without food

• Adherence, calendars, d/w patient AI is continuous

• Drug Interactions • Avoid strong CYP3A4

inhibitors/inducers

• CYP3A4 substrates with NTI may need dose reduction

• Avoid concomitant drugs known to prolong QT interval

• QT interval prolongation • ECG at baseline, cycle 1 day 14, and

cycle 2 day 1, then prn

• Electrolytes day 1 for 6 cycles

• Hepatobiliary toxicity • LFTS at baseline and every 2 weeks for

first 2 cycles

• Then day 1 of each subsequent 4 cycles

• Monitor CBC at baseline, every 2 weeks for first 2 cycles, then day 1 of each subsequent 4 cycles • Most likely to occur in first 4 weeks of

therapy

ANC Dose modification

Grade 1/2

(>1000/mm3)

No dose adj. required

Grade 3

(<1000/mm3)

Hold until ANC

(>1000/mm3, resume at

same dose unless grade 3

neutropenia recurs

Grade 3 + fever

or grade 4

(<500/mm3)

Hold until ANC

(>1000/mm3, resume at

lower dose

ANC=absolute neutrophil count

Kisqali (ribociclib) [prescribing information]

Abemaciclib

• Structurally different than the other CDK4/6 inhibitors • 14x more potent against cyclin

D1/CDK4 than cyclin D3/CDK6

• Only CKD4/6 inhibitor approved as monotherapy

• MONARCH1: abemaciclib for refractory HR(+), HER2(-) MBC • Phase II, single-arm, open-label

study

• Abemaciclib 200 mg po q 12 hours continuously until disease progression or toxicity

• Primary endpoint: ORR

Dickler MN et al. Clin Cancer Res. 2017; 23(17):5218-24.

MONARCH1: abemaciclib

Efficacy Outcomes

Overall response rate (CR+PR) 26%

Disease control rate (CR+PR+SD) 89%

Median PFS 6.0 months

Median OS 17.7 months

Safety/Adverse Events

All grade (%) Grade 3/4 (%)

Neutropenia 87.7 26.9

Diarrhea 90.2 19.7

Fatigue 65.2 12.9

AST increase 30 3.8

Alk Phos

increase

26.2 1.5

Dickler MN et al. Clin Cancer Res. 2017; 23(17):5218-24.

Abemaciclib Clinical Pearls

• Different dosing in combination with fulvestrant vs. monotherapy

• Taken with or without food

• No break; continuous dosing

• Drug Interactions • Avoid strong CYP3A inducers

• Dose reduction with strong CYP3A inhibitors • Avoid ketoconazole

• Diarrhea: should initiate antidiarrheals at first sign of diarrhea, increase fluid intake, notify HCP

• Neutropenia: monitor CBC q 2 weeks for first 2 months, then monthly x2, then prn

• Hepatotoxicity: monitor LFTS q 2 weeks for first 2 months, then monthly x2, then prn

• Venous thromboembolism risk

Verzenio (abemaciclib) [prescribing information].

Comparing the CDK4/6 Inhibitors

• NCCN recommendations (category 1) – First-line treatment option for HR(+)/HER2(-) MBC

• Palbociclib + AI

• Ribociclib + AI

– Progression on prior endocrine therapy • Abemaciclib + fulvestrant

• Palbociclib and abemaciclib also approved in combination with fulvestrant – can be used beyond first-line therapy in MBC

• Abemaciclib is continuously dosed; others are 3 weeks on/1 week off • Can be beneficial for compliance/adherence purposes

• Different adverse event profiles • Abemaciclib: less neutropenia, but more diarrhea, fatigue

• Due to relative potency for cyclin D1/CKD4 vs. cyclin D3/CDK6

• Palbociclib/Ribociclib: less GI events, but more neutropenia

• Ribociclib: QT prolongation caution


Safety Differences

Palbociclib Ribociclib

Abemaciclib

All grade

(%)

Grade 3/4

(%)

All grade

(%)

Grade 3/4

(%)

All grade

(%)

Grade 3/4

(%)

Neutropenia 80 67 74 59 41 21

Fatigue 37 2 37 2 40 2

Diarrhea 26 1 35 1 81 10

Nausea 35 <1 52 2 39 12

QT prolongation NR NR 8 0% NR NR

Febrile

neutropenia

1.8 1.5 <1

*Table adapted from studies evaluating CDK4/6 inhibitor for first-line treatment of MBC with

letrozole

Finn RS et al. N Engl J Med 2016; 375:1925-36


Goetz MP et al. J Clin Oncol. 2017; 35:3638-46.

Assessment Question #2

Which of the following CDK4/6 inhibitors is FDA approved as

monotherapy in the treatment of hormone-receptor positive advanced

breast cancer?

A. Abemaciclib

B. Ribociclib

C. Palbociclib

D. None, they all must be given in combination with endocrine

therapy

Lung Cancer

• Second most common cancer in the US in men and women

• Number one cause of cancer-related deaths

• 5 years following diagnosis, only 15% of all lung cancer patients are alive

• Small Cell Lung cancer (13-17% of all lung cancer) • Most aggressive lung tumor

• Initially has high sensitivity to radiation/chemotherapy

• Non-small cell lung cancer • Slower growing, less aggressive clinical course compared to SCLC

• Low sensitivity to chemotherapy

• Histologies: adenocarcinoma, large cell carcinoma, squamous cell carcinoma

• Resectable: stage I, II, IIIA

• Unresectable: stage IIIB

American Cancer Society. Lung Cancer Key Statistics.

Govindan R, et al. J Clin Oncol. 2006; 24(28):4539-44.

Wahbah M, et al. Ann Diagn Pathol. 2007; 11(2):89-96.

Non-small Cell Lung Cancer NCCN Guidelines V 2.2018.

Stage I-III NSCLC

Early Stage NSCLC

Stage I Stage II Stage III

Surgical resection

Surgical resection +

adjuvant

chemotherapy

Chemoradiation?

Surgery?


Stage III NSCLC

• Locally advanced disease

• Treatment dependent on ability to resect disease, findings in surgery

• For unresectable disease, standard of care is platinum-based doublet chemotherapy with concurrent radiation therapy • Carboplatin/paclitaxel + RT +/- additional 2 cycles carboplatin/paclitaxel

• Cisplatin/etoposide + RT

• Cisplatin/vinblastine + RT

• Carboplatin/pemetrexed + RT (non-squamous)

• Cisplatin/pemetrexed + RT +/- additional 4 cycles pemetrexed

• Poor outcomes: median PFS of 8 months, only 15% alive at 5 years

• No major advances in this area in many years


Auperin A, et al. J Clin Oncol. 2010; 28:2181-90.

Immunotherapy in Lung Cancer

• Programmed cell death protein 1 (PD-1) receptor is expressed on activated T-cells • It’s liga d, PD-L1, expressed on many

types of tumor cells

• Interaction of PD-1 with PD-L1 leads to tu or i u e syste escape • Tumor cells able to evade recognition

and elimination by T-cells

• PD-1/PD-L1 inhibition disrupts ability of the two to interact • Inhibition of PD-1/PD-L1 results in T-cell

reactivation

• Inhibition restores and maintains anti-tumor T-cell response

• PD-1/PD-L1 inhibition found to be safe/effect in advanced NSCLC • Nivolumab, Pembrolizumab,

Atezolizumab

• Role in early stage NSCLC?

Image borrowed from http://www.medscape.com/viewarticle/812990_10

Durvalumab

• Selective, high-affinity, human IgG1 monoclonal antibody that inhibits the binding of PD-L1 to PD-1 and CD80 • Allows T cells to then recognize and kill tumor cells

• Initially FDA-approved for treatment of advanced bladder cancer after treatment with platinum-based chemotherapy • Under accelerated approval based on tumor response rates and

duration of response

• Has demonstrated activity in stage IIIB and IV NSCLC

• Preclinical evidence that chemoradiotherapy may help upregulate PD-L1 expression in tumor cells

Stewart R, et al. Cancer Immunol Res. 2015; 3:1052-62.

Antonia SJ, et al. N Engl J Med. 2017; 377(20):1919-29.

PACIFIC: Durvalumab

consolidation

Durvalumab 10

mg/kg IV q 2 weeks

x12 months

Stratification

• Age

• Sex

• Smoking

history

2:1 Randomization

N=749

n=476

n=273

• Stage III, locally advanced,

unresectable NSCLC

• No disease progression after

chemoRT

• Good performance status

• Finished chemoRT within 6

weeks of randomization

• Exclusion: autoimmune

disease, grade 2+

pneumonitis from chemoRT

Platinum-based

chemotherapy

plus

radiation

Placebo


Multicenter, randomized, double-blind, phase III trial

PACIFIC trial: Durvalumab

consolidation

Durvalumab Placebo

Median PFS 16.8 months* 5.6 months

12-month PFS 55.9% 35.3%

18-month PFS 44.2% 27%

ORR 28.4%* 16%

Median time

to

death/distant

metastasis

23.2 months* 14.6 months

*P<0.001


PACIFIC continued

• Efficacy was independent of PD-L1 expression

• Safety – ADRs with durvalumab consistent with other immunotherapies • Pneumonitis/radiation pneumonitis higher with durvalumab (33.9% vs. 24.8%)

• Grade 3/4 ADRs higher with durvalumab (29.9% vs. 26.1%)

• Overall survival data not yet available

• FDA approved (2/16/18) for treatment of patients with stage III NSCLC whose tumors are unresectable and whose cancer has not progressed after therapy with chemoradiation • NCCN recommendations in this setting, PS 0-1, after 2 or more cycles of definitive chemoRT

• Pearls • Monitor for immune-related adverse events (TSH, LFTs, SCr, etc)

• Pneumonitis, hepatitis, immune-mediated endocrinopathies, nephritis, colitis, etc.

• IV infusion over 60 minutes, infusion-reaction risk?

• Financial toxicity – average wholesale price/month=$15,000



True or false: Lung cancer tumors must express PD-L1 in order for

patients to derive progression-free survival benefit from durvalumab

consolidation therapy.

A. True

B. False

Treatment Approach to

Stage IV NSCLC • Systemic therapy for patients with adequate performance

status

• Molecular testing for driver/actionable mutation, particularly in non-squamous NSCLC

• Lack of actionable mutation? • Platinum-based doublet chemotherapy

• Actionable mutation? • Initiate targeted therapy

o EGFR

o ALK

o ROS1

o PD-L1

o BRAF

o RET

o HER2

ALK-positive NSCLC

• Anaplastic lymphoma kinase (ALK) rearrangements present up to 8% NSCLC cases

• ALK gene is a member of the insulin receptor tyrosine kinase super family • Oncogenic fusion protein

• Originally identified in the context of anaplastic large cell lymphoma in 1994

• Discovered in 2007 that subgroup of NSCLC patients harbored ALK rearrangements

• Patients are younger, never/light smoking history, adenocarcinoma histology

• CNS is a sanctuary site for metastasis • Many of our therapies do not boast effective penetration

• Whole brain radiation therapy often used to manage CNS metastases

Thai AA, Solomon BJ. Curr Opin Oncol. 2017; 29:000-000.

Kris MG, et al. JAMA. 2014; 311:1998-2006.


ALK-positive NSCLC

• Drug target: Crizotinib, oral TKI that inhibits ALK • Crizotinib superior to platinum/pemetrexed in untreated ALK-positive NSCLC

• ORR 74% vs. 45%, PFS longer 10.9 months vs. 7 months

• However most patients develop resistance within first 12 months of therapy

• Next generation ALK inhibitor can be considered upon progression • Alectinib

• Brigatinib

• Certinib

• Cytotoxic therapy can be considered after progression on 2nd-line ALK inhibition


ALTA: Brigatinib

• Brigatinib – next-generation anti-ALK TKI, designed to overcome resistance

that may occur with other ALK inhibitors

• Phase I/II trial with promising activity in patients previously treated with crizotinib

(ORR=62%, median PFS=12.9 months)

• Multicenter, open-label, randomized, phase II trial evaluating brigatinib

following progression on crizotinib for ALK-positive NSCLC until

progression/intolerable toxicity

• LA/metastatic ALK(+) NSCLC

• Progression on crizotinib

• Any number of prior chemotherapy regimens

allowed

• Exclusion: pulmonary interstitial disease,

drug-induced pneumonitis, symptomatic CNS

mets

.

Brigatinib 90 mg po daily

Brigatinib 180 mg po daily

*7-day 90 mg daily lead-in

1:1 Randomization

N=222

n=110

n=112

Kim DW et al. J Clin Oncol. 2017; 35:2490-8.

ALTA continued

Efficacy Outcomes 90 mg daily 180 mg daily

Overall response rate 45% 54%

Median time to response 1.7 months 1.9 months

Median duration of response 13.8 months 11.1 months

Median PFS 9.2 months 12.9 months

Safety/Adverse Events 90 mg daily 180 mg daily

All grade (%) Grade 3/4 (%) All grade (%) Grade 3/4 (%)

Nausea 33 1 40 1

Respiratory (Cough, dyspnea) 39 3 55 2

Increased CPK 11 3 30 9

Hypertension 11 6 21 6

Kim DW et al. J Clin Oncol. 2017; 35:2490-8.

Brigatinib Clinical Pearls

• FDA approved for treatment of ALK(+) NSCLC in patients who have progressed on or intolerant to crizotinib • Under accelerated approval based

on tumor response and duration of response

• Take with or without food

• 90 mg/day x7 days lead-in for tolerability, then 180 mg daily if tolerated

• Avoid with strong CYP3A4 inhibitors/inducers. CYP3A4 substrates may affected

• Monitor for pulmonary ADRs • Cough, dyspnea, interstitial lung

disease/pneumonitis

• Especially during first week

• Manage with dose interruption and prompt clinical evaluation

• Monitor BP after 2 weeks and then monthly while on therapy

• Can cause bradycardia, monitor pulse

• Monitor CPK, amylase, lipase regularly during therapy

Alunbrig (brigatinib) [prescribing information].

ALEX: Alectinib vs. Crizotinib

• Alectinib – next-generation anti-ALK TKI, previously indicated after

treatment with crizotinib

• Able to penetrate the CNS

• Potentially more beneficial in ALK(+) NSCLC since CNS is most common site of

metastasis?

• Multicenter, open-label, randomized, phase II trial

• Advanced ALK(+) NSCLC

• ECOG performance status of 0-2

• No prior systemic treatment of advanced

disease

• Asymptomatic CNS mets, prior CNS

radiotherapy completed >14 days before

randomization

Alectinib 600 mg po

twice daily

Crizotinib 250 mg po

twice daily

1:1 Randomization

N=303

n=151

n=152

Stratification

• Performance

status

• Race

• CNS mets

Peters S et al. N Engl J Med 2016; 377:829-38.

ALEX continued

Efficacy Outcomes

Alectinib Crizotinib

Median PFS Not reached 11.1 months

12-month PFS 68.4% 48.7%

Duration of

Response Not estimable 11.1 months

CNS

progression 12% 45%

Safety/Adverse Events

Peters S et al. N Engl J Med 2016; 377:829-38.

Adverse Event Crizotinib Alectinib

All grade (%) Grade 3+ (%) All grade (%) Grade 3+ (%)

Nausea 48 3 14 1

Diarrhea 45 2 12 0

ALT increase 30 15 15 5

AST increase 25 11 14 5

Bilirubin increase 1 0 15 2

Myalgia 2 0 16 0

Visual impairment 12 0 1 0

Anemia 5 1 20 5

Alectinib Clinical Pearls

• FDA approved for the treatment of patients with ALK-positive NSCLC

• 600 mg po twice daily with food • Available in 150 mg capsules

• Adjust doses by 150 mg-increments for toxicity

• Alectinib and M4 (major active metabolite) metabolized by CYP3A4 • No PK interactions have been

identified though

• Hepatotoxicity: monitor LFTs q 2 weeks for first 3 months, then q month and prn

• Warnings: • Interstitial Lung Disease

• Nephrotoxicity

• Bradycardia

• Severe Myalgia/CPK elevation

Alecensa (alectinib) [prescribing information].


True or false: Brigatinib is currently FDA-approved for the treatment of

ALK-positive NSCLC for patients who have progressed on or are

intolerant to alectinib.

A. True

B. False

ALK Conclusions

• NCCN recommendations: – Alectinib now preferred over crizotinib as first line

therapy in stage IV ALK-positive NSCLC

– Alectinib, brigatinib, and ceritinib can be considered as second-line therapy following progression on crizotinib

• Uncertain future for brigatinib?

• Anti-ALK TKI therapy following progression on alectinib?

Conclusion

• A number of new pharmacotherapies have been recently approved to treat breast and lung cancers in both the curative and palliative setting

• Extended adjuvant therapy with neratinib may add further improvements in clinical outcomes in early stage HER2(+) breast cancer in select patients

• CKD4/6 inhibitors have added to the armamentarium of agents available for the treatment of HR(+), HER2(-) metastatic breast cancer

• Advances in targeted therapy and immunotherapy continues to change the landscape of managing NSCLC that provides a more precision medicine-based approach

Questions?

Thank you!

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