MM/CML/NSCLC

MM2

100

PFS

What is the primary endpoint of Tourmaline MM2

200

Definition of high risk in Tourmaline MM2

What are carrying del(17p), amp(1q21), t(4;14), or t(14;16

300

Stratification factors in Tourmaline MM2

What are: Age : > 75 years vs < 75 ; ISS: stage 1 or 2 vs stage 3 ;BPI-SF worst pain score: > 4 vs < 4 at screening

400

Dosing of ixazomib, Lenalidomide and dexamethasone in Tourmaline MM2

What is : for cycles 1-18 (or unacceptable toxicity): Ixa: 4 mg PO d 1, 8, 15 , R: 25 mg PO d 1 – 21, d: 40 mg PO weekly. After 18 cycles: Ixa: 3 mg PO d 1, 8, 15 , R: 10 mg PO d 1 – 21

500

3 Secondary endpoints in Tourmaline MM2 (not key secondary endpoints)

What are: : ORR(CR + VGPR + PR), Time to response, DOR, Time to progression, PFS2, ECOG performance scores, AEs, serious adverse events (SAEs), and assessments of clinical laboratory values . OS and PFS in high-risk population carrying del(17p), amp(1q21), t(4;14), or t(14;16), frequency of detection of MRD via flow cytometry in patients assessed at suspected CR during Cycles 1 through 17 and in patients with confirmed or suspected CR during Cycle 18, and its impact on TTP, PFS, and OS, Time to pain progression, Plasma concentration-time data to contribute to future population PK analysis, Development of new or worsening of existing skeletal-related events

Ponatinib PI

100

FDA Indication for Iclusig

What is Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated. • Treatment of adult patients with T315I-positive CML (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

200

FDA approved dose of Iclusig

What is 45 mg taken orally once daily with or without food (2.1) • Hepatic Impairment: 30 mg orally once daily (2.5) • Modify or interrupt dosing for hematologic and non-hematologic toxicity *The optimal dose of Iclusig has not been determined

300

the basis for the six cohorts in PACE

What is Patients were assigned to one of six cohorts based on disease phase (chronic phase CML [CP-CML]; accelerated phase CML [AP-CML]; or blast phase CML /Philadelphia-positive acute lymphoblastic leukemia [BP-CML/Ph+ ALL]), resistance or intolerance (R/I) to prior TKI therapy, and the presence of the T315I mutation.

400

The 4 main points in the black box warning

What is • Arterial occlusion has occurred in at least 35% of Iclusig-treated patients including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Interrupt or stop Iclusig immediately for arterial occlusion. A benefit-risk consideration should guide a decision to restart Iclusig (5.1). • Venous thromboembolism has occurred in 6% of Iclusig-treated patients. Monitor for evidence of thromboembolism. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism (5.2). • Heart failure, including fatalities, occurred in 9% of Iclusig treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure (5.3). • Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected (2.3, 5.4).

500

The most common non-hematological adverse reactions(>20%) Hint: there are 14 of them

What are abdominal pain, rash, constipation, headache, dry skin, fatigue, hypertension, pyrexia, arthralgia, nausea, diarrhea, lipase increased, vomiting, myalgia and pain in extremity

Ponatinib #2

100

Distinctive structural feature of ponatinib that?enables single point mutations in ABL kinase domain to be overcome, including the T315I gatekeeper mutant

What is triple carbon bond Ponatinib Advanced Phase Deck)

200

PACE Study Design

What is phase 2, single arm, open label trial in patients who were Resistant or intolerant to dasatinib or nilotinib OR Patients with ?T315I mutation N=449 ponatinib 45mg starting dose Primary endpoints: MCyR by 12 months for CP-CML MaHR by 6 months for AP-CML, BP-CML, and Ph+ ALL

300

Terminal elimination half life of ponatinib and predominant elimination route

What is approximately 24 hours (12-66)following 45mg administration daily for 28 days. 87% in feces, 5% in urine

400

Efficacy of Iclusig in Patients with TKI R/I Chronic Phase CML

What is MCyr overall 55% in R/I 51%, in T315I 70% CCyR: 46% overall, 40% in R/I and 66% in T315I Major Molecular response (secondary endpoint): 39% overall 34% R/I 58% T315I Table 12

500

Efficacy of Iclusig in Patients with R/I Advanced disease (including both R/I and T315I)

What is Major Hematological response at 6months 57% AP-CML; 31% BP-CML; 41% Ph+ ALL median time to MaHR was .7 1.0 and 0.7 month respectively Table 13

CML

100

Three phases of CML

What are chronic, accelerated and blast phases

200

To date, the only CML treatment that can result in a cure

What is HCT

300

Cutoffs for the three phases of CML

What is <15% blasts in chronic, 15-30% for accelerated and >30% for blast phase

400

Typical signs and Symptoms of CML

What are nausea, fatigue, weakness, abdominal fullness, weight loss/anorexia, night sweats/fever, bleeding or bruising, bone pain. Typically found upon physical exam: splenomegaly, hepatomegaly,

500

US treatment guidelines for advanced phase CML and Ph+ALL

What is for AP-CML: TKI (imatinib, dasatinib, nilotinib, bosutinib, ponatinib*); omacetaxine; Consider SCT based on response * for T315I or if pt has not responded to >2 TKI BP-CML ALL/AML-type CT + TKI → SCT TKI (imatinib, dasatinib, nilotinib, bosutinib, ponatinib*) → SCT For Ph+ALL INDUCTION THERAPY CT + TKI (imatinib or dasatinib) CONSOLIDATION THERAPY SCT ?Multi-agent CT + TKI (imatinib + dasatinib) Consider post-SCT TKI†?Maintenance therapy + TKI† †NCCN does NOT specificTKI in this indication

Miscellaneaous

100

The Three NDMM trials with proteasome inhibitors

What are SWOG0777, Endeavor, Tourmaline MM2

200

Percentage of adults and children with ALL who have PH+ disease

What is 20–30% of adults and 2–3% of children

300

selective targets of brigatinib and the company-sponsored clinical trials

What are ALK and ROS1. clinical trials: Phase 1/2, solid tumors, primarily crizotinib-resistant ALK+ NSCLC Pivotal phase 2, “ALTA”, crizotinib-resistant ALK+ NSCLC Pivotal phase 3, “ALTA 1L”, ALK TKI naïve ALK+ NSCLC, randomized against crizotinib

400

trial design and endpoints of ALTA

What is randomized phase 2 design, not intended to compare arms. Patients with locally advanced or metastatic ALK+ NSCLC; PD on crizotinib; No other ALK-directed therapy. Stratified by: Brain metastases at baseline; Best response to prior crizotinib Arm 1: Brig 90mg Arm 2: bring 180mog with 7 day 90mg lead in. Primary endpoint: Confirmed ORR per RECIST v1.1 (assessed by investigator) Key secondary endpoints: Confirmed ORR (assessed by an IRC), CNS response (IRC-assessed intracranial ORR and PFS in patients with active brain metastases†), duration of response, PFS, OS, safety, and tolerability

500

trial design and endpoints of ALTA-1L

What is a randomized, phase 3 trial Arm A: brig 180 (with run in) ArmB: crizotinib 250mg bid treatment to PD, unacceptable toxicities. Crossover from Arm B allowed at PD Additional Key Inclusion Criteria: ECOG 0-2, measurable disease, ≤1 prior regimen in the advanced setting Primary Endpoint: IRC assessed PFS per RECIST 1.1 Statistical Considerations: ~270 total patients (198 events); 135 each arm to detect a 6 month improvement in PFS (HR=0.625), assuming 10 months PFS in crizotinib arm; two planned interim analyses at 50% and 75% of total expected events have been observed.