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ModeratorNeil Love, MD

Faculty

Challenging Cases in Lung Cancer

Oncologist and Nurse Investigators Consult on Actual Patients from the

Practices of the Invited Faculty

Friday, May 2, 20146:00 AM – 7:30 AM

Rebecca Lynn Sipples, MSN, APRN, ACNP, AOCNPAlison J Holmes Tisch, MSN, RN, ANP-BP, AOCNP

Geoffrey R Oxnard, MDKaren L Reckamp, MD, MS

Oncology 6-Part Case Series: Key Themes

• Mechanisms of action of novel agents and tissue assays to predict response

• Side effects and toxicities of novel agents; dose adjustments

• Assessment and management of adherence

• Specific goals of therapy and likely outcomes; sequencing of agents in advanced disease

• Local and systemic complications of cancer: Fatigue, pain, CNS involvement

• Care of older, frail patients and those with comorbidities

Oncology 6-Part Case Series: Key Themes

• Clinical trials as a means to access new treatments earlier

• Management of anxiety and depression

• Key determinants of patient satisfaction: What do people with cancer want and need?

• Quality, value and cost: Investing resources optimally

• End-of-life care and planning

• Impact of the cancer experience on family and loved ones, including minor children

• Impact of the oncology experience on oncology health professionals

Agenda

Two Patients with Adenocarcinoma and EGFR Tumor Mutations

•54 yo woman with advanced EGFR-mutant NSCLC with progressive disease after responding to erlotinib (Ms Sipples)

•36 yo Afghani woman with advanced EGFR-mutant NSCLC currently receiving afatinib/cetuximab (Ms Tisch)

A Patient with Metastatic Adenocarcinoma Who Received Front-Line Chemobiologic Therapy Followed by Maintenance

•41 yo woman with advanced “pan-wild-type” NSCLC with 2 young children (Ms Tisch)

Agenda

A Patient Who Received Immunotherapy on a Clinical Trial

•77 yo woman with advanced NSCLC who went on a clinical trial of nivolumab and is currently receiving nanoparticle albumin-bound (nab) paclitaxel (Ms Sipples)

Two Patients with Tumor Mutations: ROS1 and HER2

•70 yo man with advanced, ROS1-mutant NSCLC receiving crizotinib (Ms Sipples)

•64 yo woman with advanced NSCLC with a HER2 insertion who has requested help with assisted suicide (Ms Tisch)

Two Patients with Adenocarcinoma and EGFR Tumor Mutations

• 54 yo woman with advanced EGFR-mutant NSCLC with progressive disease after responding to erlotinib (Ms Sipples)

• 36 yo Afghani woman with advanced EGFR-mutant NSCLC currently receiving afatinib/cetuximab (Ms Tisch)

Case 1 (from the practice of Ms Sipples)

• A 54-year-old woman was diagnosed 9 months ago with advanced non-small cell lung cancer (NSCLC) (adenocarcinoma with EGFR L858R exon 21 point mutation) and multiple ring-enhancing brain metastases

• She responded to erlotinib but then developed progressive disease

Incidence of tumor driver mutations in patients with NSCLC; algorithms for tissue testing

Discussion Point

Incidence of Single Driver Mutations in Metastatic Lung Adenocarcinoma

Kris MG et al. JAMA 2014;311(19):1998-2006.

N = 733

Selection of first-line therapy for patients with EGFR activating mutations; similarities and differences between erlotinib and afatinib

Discussion Point

Select Trials of First-Line Treatment with EGFR TKIs vs Chemotherapy in EGFR-Mutant NSCLC

Study Treatment N RR, % PFS, mo OS, mo

IPASS1,2 Gefitinib vs Carbo/pac

261 71.2 vs 47.3

9.5 vs 6.3

21.6 vs 21.9

NEJ0023 Gefitinib vs Carbo/pac

230 73.7 vs 30.7

10.8 vs 5.4

30.5 vs 23.6

OPTIMAL4,5 Erlotinib vs Carbo/gem

165 83 vs 36

13.1 vs 4.6

22.7 vs 28.9

EURTAC6 Erlotinib vs Platinum-based chemo

174 58 vs 15

9.7 vs 5.2

19.3 vs 19.5

1 Mok TS et al. N Engl J Med 2009;361(10):947–57. 2 Fukuoka M et al. J Clin Oncol 2011;29(21):2866–74. 3 Maemondo M et al. N Engl J Med 2010;362(25):2380–8. 4 Zhou C et al. Lancet Oncol 2011;12(8):735–42. 5 Zhou C et al. Proc ASCO 2012;Abstract LBA7520. 6 Rosell R et al. Lancet Oncol 2012;13(3):239–46.

Possible Erlotinib-Associated Side Effects

Most Common AEs

•Rash

•Fatigue

•Diarrhea

•Appetite loss

Afatinib: An Irreversible ErbB Family Blocker

Afatinib is an orally available, irreversible ErbB family blocker, with high efficacy potential•Inhibition of ErbB family receptor heterodimerization

•In vitro activity against EGFR-resistant T790M mutation

Adapted from Li D et al. Oncogene 2008;27:4702-11.

EGF ligands Heregulins

EGFR inhibitors

ErbB Family Blockade

EGFR (ErbB1) HER2 (ErbB2) ErbB3 ErbB4

Phase III LUX-Lung 3 Study for Patients with Treatment-Naïve Advanced Lung Cancer

Primary endpoint: PFSSecondary endpoints: ORR, DCR, DoR, tumor shrinkage, OS, patient-reported outcomes, safety, PK

Cisplatin + Pemetrexed

R2:1

Afatinib

Stage IIIB/IV lung adenocarcinoma

EGFR mutation in tumor

Yang JC et al. Proc ASCO 2012;Abstract LBA7500.

LUX-Lung 3: Response and PFS (Independent Review)

Afatinib(n = 230)

Cis/pem(n = 115)

Response rate 56% 23%

Median progression-free survival

11.1 mo 6.9 mo

Sequist LV et al. J Clin Oncol 2013;31(27):3327-34.

Possible Afatinib-Related AEs

Most Common AEs

•Diarrhea

•Rash/acne

•Stomatitis/mucositis

•Paronychia

•Dry skin

Sequist LV et al. J Clin Oncol 2013;31(27):3327-34.

Mechanisms of resistance to EGFR TKI therapy

Discussion Point

LUX-Lung 1 Phase IIb/III Study of Afatinib After Failure of Erlotinib, Gefitinib or Both and Chemotherapy

• N = 585 patients with Stage IIIB/IV adenocarcinoma of the lung

• Afatinib/best supportive care (BSC) vs placebo/BSC• All received prior EGFR TKI and chemotherapy

Miller VA et al. Lancet Oncol 2012;13(5):528-38.

Afatinib Placebo

Median OS 10.8 mo 12.0 mo

Median PFS 3.3 mo 1.1 mo

ORR 7% <1%

No complete responses

Phase II Study of Afatinib/Cetuximab

Afatinib +Cetuximab

• EGFR mutant

• Advanced NSCLC

• Progressing on erlotinib or gefitinib

• N = 100

ORR: 30%Median PFS: 4.7 moMedian DoR: 8 moGrade 3 Rash: 18%Grade 3 Diarrhea: 7%

Janjigian YY et al. Proc ESMO 2012;Abstract 1227O.

Afatinib + cetuximab at MTD: Responses by T790M mutation

5040302010

0–10–20–30–40–50–60–70–80–90

–100–110

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100Patient index sorted by maximum % decrease

Max

imum

per

cent

age

de

cre

ase

from

ba

selin

e (%

)

T790M+ T790M– EGFR wt Uninformative for T790M

With permission from Janjigian YY et al. Proc ESMO 2012;Abstract 12007O.

Response

T790 Mutation Status

Total(n = 96)

T790M+(n = 53)

T790M-(n = 39)

Clinical benefit rate 81% 64% 75%

Median duration of response

6.4 mo 9 mo 8 mo

Best Response Rates

Janjigian YY et al. Proc ESMO 2012;Abstract 12007O.

Case 2 (from the practice of Ms Tisch)

• A 36-year-old Afghani woman was initially diagnosed in June 2005 with bronchoalveolar carcinoma that has since been categorized as adenocarcinoma with lepidic features

• The patient’s disease has progressed through multiple treatments including chemotherapy, erlotinib, bevacizumab and 2 clinical trials, one of a single-agent investigational tyrosine kinase inhibitor (TKI) and one of erlotinib combined with cabozantinib

• She was later enrolled on a clinical trial of CO-1686 and experienced a life-threatening tumor flare reaction after discontinuation of the drug, which was reversed by restarting erlotinib

• She is currently receiving cetuximab and afatinib• The patient is a married mother of young children• Her Muslim faith plays a strong role in her desires

concerning possible future end-of-life care

Progressive Disease on a Trial of CO-1686

Partial Response After Retrial with Erlotinib

Progressive Disease After Retrial of Erlotinib

Partial Response to Cetuximab and Afatinib

CO-1686

• Mutation-specific TKI targeting activating mutations and T790M

• Theoretically offers key advantage by not inhibiting wild-type EGFR

• 45 2nd-line TKI patients, 74% T790M+• Notably absent was rash and diarrhea• Clinical responses have been observed in 3 of 4

patients who received the highest dose• Phase II and III studies are under development

Soria JC et al. Proc WCLC 2013;Abstract O03.06.

Skin Rash from Tyrosine Kinase Inhibitors

• Most frequent dermatologic side effect reported is acneiform eruption.

• Affects mainly face, upper chest and/or back.

• Also known as acne, acneiform skin reaction/rash, follicular rash and maculopapular skin rash.

Ricciardi S et al. Clin Lung Cancer 2009;10(1):28-35.

Clinical Grades of Erlotinib-Induced Rash

• Mild– Generally localized papulopustular reaction– Minimally symptomatic– No impact on daily activities– No sign of superinfection

• Moderate– Generalized papulopustular reaction– Mild pruritus or tenderness– Minimal impact on daily activities– No sign of superinfection

• Severe– Generalized papulopustular reaction– Severe pruritus or tenderness– Significant impact on daily activities– Potential for or has become superinfected

Saif MW et al. JOP 2008;9(3):267-74.

Case 3 (from the practice of Ms Tisch)

• A 41-year-old woman was diagnosed in 2010 with a Stage IIIA adenocarcinoma that was treated with cisplatin/pemetrexed followed by right upper lobectomy and then consolidative chemoradiation therapy

• In 2011 she experienced systemic disease recurrence and was started on carboplatin/paclitaxel/bevacizumab followed by maintenance bevacizumab

• The patient is married with 2 young children

2011: Systemic Disease Recurrence

Response to Carboplatin/Paclitaxel/Bevacizumab Prior to Maintenance Therapy

Systemic treatment of metastatic “pan-wild-type” NSCLC: Choice of chemotherapy regimen and role of bevacizumab

Discussion Point

Chemotherapeutic Regimens Commonly Employed in the Front-Line Management of Metastatic Pan-Wild-Type NSCLC

• Carboplatin/paclitaxel ± bevacizumab

• Carboplatin/nab paclitaxel ± bevacizumab

• Carboplatin/pemetrexed ± bevacizumab

• Cisplatin/chemotherapy ± bevacizumab

NCCN NSCLC Clinical Practice Guidelines v 3.2014

ECOG-E4599: Bevacizumab in Nonsquamous NSCLC

Paclitaxel/carboplatin/

bevacizumab(n = 443)

Paclitaxel/carboplatin

(n = 444)

Median progression-free survival (PFS)

6.2 months 4.5 months

Median overall survival (OS)1-yr OS2-yr OS

12.3 months51%23%

10.3 months44%15%

Sandler A et al. N Engl J Med 2006;355(24):2542-50.

Recognition and management of hypertension and proteinuria with bevacizumab; risk of cardiovascular events

Discussion Point

Maintenance strategies in NSCLC: biologic therapy, chemotherapy or both

Discussion Point

What Is Maintenance Therapy?

• Use of systemic therapy following 1st-line therapy, for patients with CR/PR/SD, before documentation of progression – Continuation of a targeted agent– Continuation of one of the agents used in the 1st-

line combination regimen– Switch to a new agent after 1st-line therapy

Rogerio C Lilenbaum, MD, Winter Lung Cancer Conference 2014

Inclusion:- No prior systemic

therapy for lung cancer

- PS 0/1

- Stage IIIB-IV NS-NSCLC

- Stable tx’t brain mets

Exclusion:- Peripheral neuropathy

≥Grade 1

- Uncontrolled pleural effusions

PointBreak: Phase III Trial Design

Induction Phase Maintenance Phase

Pemetrexed + Carboplatin

+ Bevacizumab

Paclitaxel + Carboplatin

+ Bevacizumab

Patel JD et al. J Clin Oncol 2013;31(34):4349-57.

Pemetrexed + Bevacizumab

Bevacizumab

R

Eligibility

• Stage IIIB/IV nonsquamous NSCLC

• No brain metastases

• Stable or better response after 4 courses of carbo, paclitaxel and bev

R

Bevacizumab

Pemetrexed

Target Accrual: 1,282

Study is currently recruiting participantsStudy Start Date: August 2010

www.clinicaltrials.gov, May 2014

Primary Endpoint: Overall survivalInduction therapy: Carboplatin, paclitaxel and bevacizumab

ECOG-E5508: A Phase III Study of Maintenance Bevacizumab, Pemetrexed or the Combination in Advanced NSCLC

Bevacizumab + Pemetrexed

Maintenance therapy

Case 4 (from the practice of Ms Sipples)

• A 77-year-old woman diagnosed in 1982 with early-stage NSCLC experienced disease recurrence in the right upper lobe in 2011, for which she underwent a segmentectomy followed by adjuvant cisplatin/pemetrexed

• Her disease recurred in May 2012, at which time she received carboplatin/gemcitabine

• After further disease progression, in April 2013 she was enrolled on a clinical trial of an immune checkpoint inhibitor but 2 months later developed brain metastases, which were resected

• Since June 2013 she has been receiving nab paclitaxel 3 out of 4 weeks and has responded well but has developed neuropathy within the past month

Adjuvant therapy for NSCLC: Choice of platinum doublet in older patients

Discussion Point

Available data with nab paclitaxel in lung cancer

Discussion Point

Chemo-naïve

PS 0-1

Stage IIIb/IV NSCLC

N = 1,052

Stratification factors:

• Stage (IIIb vs IV)

• Age (<70 vs >70)

• Histology (squamous vs nonsquamous)

Nab Paclitaxel 100 mg/m2 d1, 8, 15Carboplatin AUC 6 d1 q3wk

No Premedicationn = 521

1:1Paclitaxel 200 mg/m2 d1 q3wkCarboplatin AUC 6 d1 q3wk

With Premedication of Dexamethasone +

Antihistaminesn = 531

Socinski MA et al. J Clin Oncol 2012;30(17):2055-62.

Phase III Nab P/C vs P/C Study Design

Common Treatment-Related ≥Grade 3 Adverse Events

Socinski MA et al. J Clin Oncol 2012;30(17):2055-62.

Nab Paclitaxel(n = 514)

Standard Paclitaxel(n = 524)

Adverse event Grade 3 Grade 4 Grade 3 Grade 4 p-value

Neutropenia 33% 14% 32% 26% <0.001

Thrombocytopenia 13% 5% 7% 2% <0.001

Anemia 22% 5% 6% <1% <0.001

Sensory neuropathy 3% 0% 11% <1% <0.001

Socinski MA et al. J Clin Oncol 2012;30(17):2055-62; Socinski MA et al. ASCO 2010;Abstract 7511.

Objective Responses by HistologyP

erc

en

t Re

spo

nse

s

Squamous NonsquamousP < 0.001 P = 0.060 P = 0.808 P = 0.069

Nab P/C

P/C

n = 228 n = 221 n = 292 n = 310

Response and Survival in Elderly Patients (≥70)

EndpointNab P/C(n = 74)

P/C(n = 82)

Overall response rate 34% 24%

Median progression-free survival 8 mo 6.8 mo

Median overall survival 19.9 mo 10.4 mo

Adverse events similar in both groups

• Nab paclitaxel- Less neuropathy- Less neutropenia- Less arthralgia- More anemia

Socinski MA et al. Ann Oncol 2013;24(2):314-21.

Anti-PD-1 and anti-PD-L1 antibodies: Mechanisms of action, predictors of response, time sequence of antitumor benefit, side effects and toxicities

Discussion Point

Role of PD-1 in Suppressing Antitumor Immunity

• Blocking PD-L1 restores T-cell activity, resulting in tumor regression in preclinical models

• Binding to PD-L1 leaves PD-1/PD-L2 interaction intact and may enhance efficacy and safety

Adapted from Spigel et al. Proc ASCO 2013;Abstract 8008.

Tumor cell Patient’s T cells

MHC TCR

PD-1

B7.1

PD-L1

MHC TCR

PD-1

B7.1

PD-L1

+ Anti-PD-L1

EngineeredFc-domain

T cell

T cells

T-cellblockade

T-cellactivation

Tumor cell growth

Tumor cell death

Granzymes and perforin

Activity of Nivolumab in Patients with Treatment-Refractory Cancer

• Two patients with lung cancer who received 10 mg/kg of nivolumab experienced unconfirmed responses, and 8 additional patients with melanoma, lung cancer or renal cell cancer had a persistent reduction in baseline target lesions in the presence of new lesions, a finding consistent with an immune-related response pattern.

• In patients with lung cancer, 14 objective responses were observed.

• All 14 patients with objective responses started treatment 24 weeks or more before data analysis, and 8 of these patients had a response that lasted 24 weeks or more. Five of 14 patients with objective responses started treatment 1 year or more before data analysis, 2 of whom had a response that lasted 1 year or more. Stable disease lasting 24 weeks or more was observed in 5 patients with lung cancer.

Topalian SL et al. N Engl J Med 2012;366(26): 2443-54.

Clinical Development of Inhibitors of PD-1 Immune Checkpoint

Target Antibody Molecule Development

stage

PD-1 Nivolumab (BMS-936558/MDX-1106/ON

O-4538)

Fully human IgG4 mAb

Phase II multiple tumors

Pidilizumab (CT-011) Humanized IgG1 mAb Phase II multiple

tumors

Lambrolizumab (MK-3475)

Humanized IgG4 mAb Phase I

AMP-224B7-DC/IgG1 fusion

proteinPhase I

PD-L1 MDX-1105/BMS-936559

Fully human IgG4 mAb

Phase I

Giaccone G. Proc ASCO Clinical Science Symposium.

Two Patients with Tumor Mutations: ROS1 and HER2

• 70 yo man with advanced, ROS1-mutant adenocarcinoma of the lung receiving crizotinib (Ms Sipples)

• 64 yo woman with advanced NSCLC with a HER2 insertion (Ms Tisch)

Case 5 (from the practice of Ms Sipples)

• A 70-year-old man with a history of Stage IIB lung adenocarcinoma treated in 2006 with resection and adjuvant cisplatin/vinorelbine experienced local recurrence 4 years ago and received chemoradiation therapy

• In 2013 the patient developed biopsy-confirmed metastatic lung adenocarcinoma positive for ROS1 mutation

• He is currently receiving crizotinib but experienced acute renal injury that led to a treatment interruption

• The patient is married and is well known by the medical staff because his daughter was a patient for breast cancer in the past

ALK and ROS tumor rearrangements: Indications for testing

Discussion Point

EML4-ALK and ROS1 Alterations in NSCLC

EML4-ALK alterations1

•In ~4% of NSCLC cases•Enriched in younger, never or light smokers with adenocarcinoma•Rarely overlaps with EGFR and K-ras mutations

ROS1 alterations2-3

•In ~1% of NSCLC cases•Enriched in younger, never or light smokers with adenocarcinoma•No overlap with other oncogenic drivers

1 Soda M et al. Nature 2007;448(7153):561-6; 2 Bergethon K et al. J Clin Oncol 2012;30(8):863-70; 3 Takeuchi K et al. Nat Med 2012;18(3):378-81.

ALK Rearrangement in Cancer

Cancer Genome Atlas, National Cancer Institute

• Chromosomal translocation most common ALK abnormality in cancer

• Rearrangement of genetic info when parts of one chromosome break off and fuse with another or flip around (inversion)

• Results in new gene and expression of fusion protein

Efficacy of crizotinib in patients with ALK and ROS rearrangements; unique toxicities associated with crizotinib: Vision abnormalities, hypogonadism

Discussion Point

Activity of Crizotinib in ALK+ NSCLCUpdate of the Phase II Study

Kim DW et al. Proc ASCO 2012;Abstract 7533.

Variable (n = 259) Crizotinib 250 mg, n (%)

Objective response rate 155 (59.8)

Complete response 4 (1.5)

Partial response 151 (58.3)

Stable disease 69 (26.6)

Objective progression 19 (7.3)

FDA NEWS RELEASEApril 29, 2014

“The US Food and Drug Administration today granted accelerated approval to ceritinib for patients with a certain type of late-stage (metastatic) non-small cell lung cancer (NSCLC).

“Ceritinib is an anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor that blocks proteins that promote the development of cancerous cells. It is intended for patients with metastatic ALK-positive NSCLC who were previously treated with crizotinib, the only other approved ALK tyrosine kinase inhibitor.”

www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm395299.htm

Shaw AT et al. N Engl J Med 2014;370(13):1189-97.

Ceritinib (LDK378) Induces Responses in the Majority of Crizotinib-Resistant Patients

• A total of 114 patients with NSCLC received at least 400 mg of ceritinib daily

• Overall response rate (ORR) was 58%

• Confirmed complete response: 1(1%)

• Confirmed partial response: 65 (57%)

• The majority of patients with NSCLC who received ceritinib had previously received crizotinib: 83/122 (68%)

• Among patients who previously received crizotinib, ORR = 56%

• Among patients who had not received crizotinib previously and who received ceritinib at ≥400 mg daily, ORR = 21/34 (62%)

Typical Responses to Ceritinib (LDK378)

• In the Phase I study of ceritinib in ALK-rearranged NSCLC, some patients experienced rapid responses to crizotinib.– In one patient with crizotinib-resistant disease,

the comparison of positron emission tomography scans taken at baseline and 3.5 weeks of ceritinib treatment was dramatic.

– Subsequent computed tomography scans after 6 weeks of ceritinib treatment showed a 52% reduction in tumor burden in this patient.

Shaw AT et al. N Engl J Med 2014;370(13):1189-97.

Case 6 (from the practice of Ms Tisch)

• A 64-year-old woman diagnosed with Stage IIIA NSCLC underwent treatment with neoadjuvant chemotherapy followed by resection and chemoradiation therapy

• Six months later metastases were detected• The patient’s disease progressed on several lines of

therapy, and interim mutational testing revealed a HER2 insertion

• She began treatment with vinorelbine/trastuzumab and had a significant clinical response and prolonged benefit but ultimately experienced clinical worsening and entered hospice

• The patient repeatedly asked for help with assisted suicide, which she planned to use near the time of her death so that she would not suffer

Pre- and Post-vinorelbine and trastuzumab treatment

Prior to treatment Post treatment

HER2 in Lung CancersAgents Targeting HER2Amplification and Protein Expression

• Trastuzumab• Pertuzumab• Lapatinib• Ado-Trastuzumab Emtansine

Trials of Investigational Agents Targeting HER2 Mutations

• Dacomitinib• Afatinib• Neratinib• Neratinib + Temsirolimus

Role of multiplex testing to identify other lung cancer mutations: Implications for clinical trial referral and nonprotocol care

Discussion Point

Options for Molecular Profiling

• Actionable Analysis (EGFR, ALK, ROS)• SNaPshot (Iafrate MGH)

– Genotyping of approx 100 key mutations• Extensive Mutation Analysis of COSMIC Genes

– Foundation Medicine 400– Sklar 409

• Whole Exome Sequencing (23,000 genes)• Whole Genome Sequencing