51-YEAR-OLD FEMALE WITH STAGE IV NON-SMALL CELL LUNG CANCER WITH RAPIDLY PROGRESSING DISEASE*

Transcription

1 CLINICAL CASE PRESENTATION 51-YEAR-OLD FEMALE WITH STAGE IV NON-SMALL CELL LUNG CANCER WITH RAPIDLY PROGRESSING DISEASE* Clinical Case Presentation By: David Ross Camidge, MD, PhD Professor, Division of Medical Oncology; Joyce Zeff Chair in Lung Cancer Research, Director of Thoracic Oncology University of Colorado Cancer Center * Aggressive disease is defined by those patients who were primary platinum refractory (patients whose best response was progressive disease) or patients with rapidly progressing disease (time-to-progression within 9 or 12 weeks) after starting initial platinum-based treatment. 1, 2 INDICATION, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving. WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue in patients who experience severe bleeding. Gastrointestinal Perforation: can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue in patients who experience a gastrointestinal perforation. Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue therapy in patients with impaired wound healing. Withhold prior to surgery and discontinue if a patient develops wound healing complications. Please see Important Safety Information, including a Boxed Warning for hemorrhage, gastrointestinal perforation, and impaired wound healing, on pages 6-7 and accompanying full Prescribing Information for.

2 Dr. Camidge Presents a Challenging Clinical Case of a Patient with Rapidly Progressing Disease* History of Present Illness A 51-year-old Caucasian female presents with a painless lump in her left deltoid and no other signs or symptoms. X-ray reveals a 5-cm soft tissue mass. Biopsy reveals a TTF-1 positive adenocarcinoma with a G12C KRAS mutation. Staging investigations (CT chest/abdomen/pelvis and MRI brain) reveal the intra-muscular mass in the left deltoid, together with subcutaneous deposits in the back and thigh, a 5-cm right lower lobe spiculated mass, bilateral bulky mediastinal lymphadenopathy and a 4-cm right adrenal mass (T2aN3M1b). PD-L1 staining using the 22C3 antibody reveals a proportion score of 0%. Past Medical History Ex-smoker (10 pack years, quit 10 years previously) No significant past medical history Taking no medications Social History She is a single mother and has a supportive friend who comes with her to most appointments She supports her 2 children (aged 8 and 12, two boys) She owns a small cleaning service Initial Treatment She commences platinum-based treatment with pemetrexed but has clinical progression (enlarging deltoid lesion) soon after completing the second cycle and repeat imaging confirms widespread progression with new and enlarging lesions including a significant increase in her soft tissue and lymph node disease, collapse of her right lower lobe and new liver lesions. Physical Exam/Review of Symptoms at Progression Despite her symptoms, she still has good performance status (ECOG PS 1) Tumor was PD-L1 negative by immunohistochemistry (TPS <1%) Patient has a persistent but largely stable left deltoid mass and is taking an opioid to control her pain She has some sense of pressure behind her sternum and some of her subcutaneous deposits are becoming painful Response Assessment/Follow-Up Imaging Imaging shows 4 lesions within the liver (the largest at 1.5 cm), a 5.5-cm right adrenal mass, a 4.5-cm right lower lobe mass with surrounding lobar collapse and bilateral mediastinal lymph nodes (the largest with a short axis of 2.5 cm). Subcutaneous nodules are now present in 4 separate places, the largest at 9 mm. The deltoid mass has had minor shrinkage and is 3.5 cm. Her CEA (elevated at baseline) has doubled during her time on chemotherapy. Patient Attitude/Characteristics Her goal is to live as long as possible to support her children and she is determined to do whatever she can to actively treat her cancer She is concerned with regard to her disease, which is progressing after only two cycles, and the fact that she can feel and see several deposits under her skin and feel the sense of pressure in her chest She feels it critical the next treatment helps her cancer shrink and does something to slow her progression, and ultimately help her live longer Treatment Plan Biomarker-driven therapies (including anti-pd-1) were considered. After reviewing her treatment options, ramucirumab 10 mg/kg and docetaxel 75 mg/m 2 IV every three weeks were commenced Clinical Case Presentation by: David Ross Camidge, MD, PhD Professor, Division of Medical Oncology; Joyce Zeff Chair in Lung Cancer Research, Director of Thoracic Oncology University of Colorado Cancer Center Hemorrhage Why adding may be appropriate Patient presents with rapidly progressing disease She has a good performance status, with an ECOG PS of 1 This young woman wants to delay tumor growth and is willing to do what it takes to actively treat her aggressive disease She understands the risks associated with therapy, but she has had disease progression on initial platinum-based chemotherapy and is determined to continue treatment This is a hypothetical patient case based on the author s clinical experience with in combination with docetaxel for mnsclc. *This clinical case presentation has been sponsored by Eli Lilly and Company. Aggressive disease is defined by those patients who were primary platinum refractory (patients whose best response was progressive disease) or patients with rapidly progressing disease (time-to-progression within 9 or 12 weeks) after starting initial platinum-based treatment. 1, 2 CEA=carcinoembryonic antigen; CT=computerized tomography; IV=intravenous; KRAS=Kirsten rat sarcoma viral oncogene homolog; MRI=magnetic resonance imaging; PD-1=programmed cell death 1; PD-L1=programmed death-ligand 1; PS=performance status; TPS=tumor proportion score; TTF-1=thyroid transcription factor 1. increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In study 3, which evaluated plus docetaxel in metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other antiplatelet therapy other than oncedaily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown. Permanently discontinue in patients who experience severe bleeding. Please see Important Safety Information, including a Boxed Warning for hemorrhage, gastrointestinal perforation, 2 and impaired wound healing, on pages 6-7 and accompanying full Prescribing Information for. 3

3 Demonstrated Significant Improvements in OS, PFS, and ORR in the REVEL Trial Population When Added to Docetaxel 3 With Consistent Results in Patients With Rapidly Progressing Disease 5 Exploratory Subgroup Analysis: ITT POPULATION (N=1253) 10.5 OS Major Outcome Measure (95% CI)* MONTHS MONTHS (9.5, 11.2) (8.4, 10.0) Hazard ratio 0.86 (95% CI: 0.75, 0.98); P=0.024 PFS (95% CI) MONTHS MONTHS (4.2, 5.4) (2.8, 3.9) Hazard ratio 0.76 (95% CI: 0.68, 0.86); P<0.001 ORR (95% CI) 3 23% (20, 26) P<0.001 CI=confidence interval; ITT=intent to treat; ORR=objective response rate; OS=overall survival; PFS=progression-free survival. * The percentage of deaths at the time of analysis was 68% (428 patients) and 73% (456 patients) in the plus docetaxel and placebo plus docetaxel arms, respectively. Median. The percentage of events at the time of analysis was 89% (558 patients) and 93% (583 patients) in the plus docetaxel and placebo plus docetaxel arms, respectively. Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) ORR=complete + partial response; does not include stable disease. 14% (11, 17) REVEL Trial Design (N=1253) 3, 4 The phase III REVEL trial evaluated the efficacy and safety of plus docetaxel vs placebo plus docetaxel in patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measures were PFS and ORR. All patients were required to have Eastern Cooperative Oncology Group performance status 0 or 1. Patients were randomized 1:1 to receive either 10 mg/kg (n=628) or placebo (n=625), in combination with docetaxel at 75 mg/m 2 every 21 days. PATIENTS WITH RAPID PROGRESSION (95% CI) OS ** OS PROBABILITY (n=71) 8.3 months # (5.2, 10.8) 9 (n=133) 5.8 MONTHS # (4.3, 7.5) (n=111) (n=98) (n=62) 4.8 months # (3.1, 6.9) Unstratified HR 0.69 (95% CI: 0.47, 1.01) (n=111) 9.1 months # (6.7, 10.8) 3.0 months # 1.5 months # 3.6 months # PFS (2.7, 4.1) (1.4, 1.9) (2.8, 4.2) Unstratified HR 0.69 (95% CI: 0.48, 0.98) OS Major Outcome Measure (95% CI) 9.1 MONTHS # (6.7, 10.8) TIME FROM RANDOMIZATION (MONTHS) Unstratified HR 0.74 (95% CI: 0.54, 1.00) (n=209) (n=98) 5.8 months # (4.3, 7.5) Unstratified HR 0.74 (95% CI: 0.54, 1.00) 1.6 months # (1.5, 2.6) Unstratified HR 0.73 (95% CI: 0.55, 0.97) (n=209) The labeling for contains a Boxed Warning for: hemorrhage, including severe and sometimes fatal events; gastrointestinal (GI) perforation, a potentially fatal event; and impaired wound healing. should be permanently discontinued in patients who experience severe bleeding or a GI perforation. should be withheld prior to surgery and discontinued if a patient develops wound healing complications. contains additional Warnings and Precautions for arterial thromboembolic events, which are sometimes fatal; hypertension; infusion-related reactions; clinical deterioration in patients with Child-Pugh B or C cirrhosis; reversible posterior leukoencephalopathy syndrome; proteinuria including nephrotic syndrome; thyroid dysfunction; and embryofetal toxicity. The most commonly reported adverse reactions (all grades; grade 3/4) occurring in 5% of patients receiving plus docetaxel and 2% higher than placebo plus docetaxel in study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; <1% vs <1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs <1%), thrombocytopenia (13% vs 5%; 3% vs <1%), lacrimation increased (13% vs 5%; <1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%). The most common serious adverse events with plus docetaxel in study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel. Please see Important Safety Information, including a Boxed Warning for hemorrhage, gastrointestinal perforation, and impaired wound healing, on pages 6-7 and accompanying full Prescribing Information for. 18% 3% 19% ORR Aggressive disease is defined by those patients who were primary platinum refractory (patients whose best response was progressive disease) or patients with rapidly progressing disease (time-to-progression within 9 or 12 weeks) after starting initial platinum-based treatment. 1, 2 The percentage of deaths at the time of analysis in the plus docetaxel arm was 75.7% (84 patients) and 80.6% (79 patients) in the placebo plus docetaxel arm. 5 # Median. ** For 9 weeks: The percentage of deaths at the time of analysis in the plus docetaxel arm was 77.5% (55 patients) and 82.3% (51 patients) in the placebo plus docetaxel arm. 5 For 12 weeks: The percentage of deaths at the time of analysis in the plus docetaxel arm was 75.7% (84 patients) and 80.6% (79 patients) in the placebo plus docetaxel arm. 5 For 9 weeks: The percentage of events at the time of analysis in the plus docetaxel arm was 93% (66 patients) and 91.9% (57 patients) in the placebo plus docetaxel arm. 5 For 12 weeks: The percentage of events at the time of analysis in the plus docetaxel arm was 91% (101 patients) and 92.9% (91 patients) in the placebo plus docetaxel arm. 5 REVEL EXPLORATORY ANALYSES 1, 6 The REVEL trial was not adequately powered, nor error-controlled, for subgroup analyses. Treatment differences observed in these subgroups cannot be regarded as statistically significant. The analyses described here were exploratory. 4 5 (10, 29) (0.4, 11) (12, 28) 9% (4, 17)

4 IMPORTANT SAFETY INFORMATION FOR WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue in patients who experience severe bleeding. Gastrointestinal Perforation: can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue in patients who experience a gastrointestinal perforation. Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue therapy in patients with impaired wound healing. Withhold prior to surgery and discontinue if a patient develops wound healing complications. Warnings and Precautions Hemorrhage increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In study 3, which evaluated plus docetaxel in metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other antiplatelet therapy other than oncedaily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown. Permanently discontinue in patients who experience severe bleeding. Arterial Thromboembolic Events (ATEs) Serious, sometimes fatal, ATEs including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials. Permanently discontinue in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving plus docetaxel (6%) as compared to placebo plus docetaxel (2%). Control hypertension prior to initiating treatment with. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend for severe hypertension until medically controlled. Permanently discontinue if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions (IRRs) Prior to the institution of premedication recommendations across clinical trials of, IRRs occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue for grade 3 or 4 IRRs. Gastrointestinal Perforations is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. In study 3, the incidence of gastrointestinal perforation was 1% for plus docetaxel versus 0.3% for placebo plus docetaxel. Permanently discontinue in patients who experience a gastrointestinal perforation. Impaired Wound Healing Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. has not been studied in patients with serious or nonhealing wounds., as an antiangiogenic therapy, has the potential to adversely affect wound healing. Discontinue therapy in patients with impaired wound healing. Withhold prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue until the wound is fully healed. Clinical Deterioration in Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent. Use in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported at a rate of <0.1% in clinical studies with. Confirm the diagnosis of RPLS with MRI and discontinue in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death. Proteinuria Including Nephrotic Syndrome Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during therapy. Withhold for urine protein levels that are 2 g over 24 hours. Reinitiate at a reduced dose once the urine protein level returns to <2 g over 24 hours. Permanently discontinue for urine protein levels >3 g over 24 hours or in the setting of nephrotic syndrome. Thyroid Dysfunction Monitor thyroid function during treatment with. Embryofetal Toxicity Based on its mechanism of action, can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with and for at least 3 months after the last dose of. Most Common Adverse Reactions The most commonly reported adverse reactions (all grades; grade 3/4) occurring in 5% of patients receiving plus docetaxel and 2% higher than placebo plus docetaxel in study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; <1% vs <1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs <1%), thrombocytopenia (13% vs 5%; 3% vs <1%), lacrimation increased (13% vs 5%; <1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%). The most common serious adverse events with plus docetaxel in study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel. In patients 65 years of age, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years of age, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for plus docetaxel and 26 (6%) deaths for placebo plus docetaxel. Treatment discontinuation due to adverse reactions occurred more frequently in plus docetaxeltreated patients (9%) than in placebo plus docetaxeltreated patients (5%). The most common adverse events leading to treatment discontinuation of were infusion-related reaction (0.5%) and epistaxis (0.3%). For patients with nonsquamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of grade 3 pulmonary hemorrhage was 1% for plus docetaxel compared to 6% overall incidence and 1% for grade 3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of grade 3 pulmonary hemorrhage was 2% for plus docetaxel compared to 12% overall incidence and 2% for grade 3 pulmonary hemorrhage for placebo plus docetaxel. Clinically relevant adverse reactions reported in 1% and <5% of plus docetaxel-treated patients in study 3 were hyponatremia (4.8% plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% plus docetaxel versus 0.8% placebo plus docetaxel). Drug Interactions No pharmacokinetic interactions were observed between ramucirumab and docetaxel. Use in Specific Populations Pregnancy: Based on its mechanism of action, can cause fetal harm. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on use in pregnant women to inform any drugassociated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and infant development, and to use effective contraception during therapy and for at least 3 months following the last dose of. Lactation: Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with. Females of Reproductive Potential: Advise females of reproductive potential that based on animal data may impair fertility. Please see accompanying full Prescribing Information for, including Boxed Warnings for hemorrhage, gastrointestinal perforation, and impaired wound healing. RB-L HCP ISI 17SEP2015 References: 1. Reck M, Paz-Ares L, Bidoli P, et al. Exploratory subgroup analysis of patients refractory to first-line chemotherapy from REVEL, a randomized phase III study of docetaxel with ramucirumab or placebo for second-line treatment of stage IV non-small-cell lung cancer. Poster presented at: Annual Meeting of American Society of Clinical Oncology; June 3-7, 2016; Chicago, IL. Abstract Data on file. Eli Lilly and Company. ONC a. 3. (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; Garon EB, Ciuleanu T-E, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944): Data on file. Eli Lilly and Company. ONC d. 6. Data on file. Eli Lilly and Company. ONC c. 6 7

5 ABOUT THE PRESENTER DAVID ROSS CAMIDGE, MD, PhD Dr. Camidge is the Director of Thoracic Oncology at the University of Colorado. His focus is in Thoracic Malignancies and Developmental Therapeutics (Phase I studies). In 2012, he was announced as the recipient of the 5th Bonnie J. Addario Lectureship as a Luminary in the quest to eradicate lung cancer. In 2013, he became the first physician to receive the Hank Baskett Sr. Spirit Award, for which he was credited as being one of the leading minds in lung cancer today. In 2015, he became the inaugural holder of the Joyce Zeff Chair in Lung Cancer Research at the University of Colorado Cancer Center, and in 2016, the Lung Cancer Foundation presented him with the Breath Away From The Cure Award, describing him as simply one of the best in treating lung cancer today. Dr. Camidge has been principal investigator on numerous clinical trials in early phase drug development and thoracic malignancies. He has authored more than 150 articles and reviews in peer-reviewed journals such as Cancer, Journal of Clinical Oncology, Journal of Thoracic Oncology, and The New England Journal of Medicine. He has presented his research at multiple national and international scientific meetings. PP-RB-US /2017 Lilly USA, LLC All rights reserved. is a registered trademark owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates.